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1
Ahmad, Azaz, Stephanie Strohbuecker, Claudia Scotti, Cristina Tufarelli, and Virginie Sottile. "In Silico Identification of SOX1 Post-Translational Modifications Highlights a Shared Protein Motif." Cells 9, no. 11 (November 13, 2020): 2471. http://dx.doi.org/10.3390/cells9112471.
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The transcription factor SOX1 is a key regulator of neural stem cell development, acting to keep neural stem cells (NSCs) in an undifferentiated state. Postnatal expression of Sox1 is typically confined to the central nervous system (CNS), however, its expression in non-neural tissues has recently been implicated in tumorigenesis. The mechanism through which SOX1 may exert its function is not fully understood, and studies have mainly focused on changes in SOX1 expression at a transcriptional level, while its post-translational regulation remains undetermined. To investigate this, data were extracted from different publicly available databases and analysed to search for putative SOX1 post-translational modifications (PTMs). Results were compared to PTMs associated with SOX2 in order to identify potentially key PTM motifs common to these SOXB1 proteins, and mapped on SOX1 domain structural models. This approach identified several putative acetylation, phosphorylation, glycosylation and sumoylation sites within known functional domains of SOX1. In particular, a novel SOXB1 motif (xKSExSxxP) was identified within the SOX1 protein, which was also found in other unrelated proteins, most of which were transcription factors. These results also highlighted potential phospho-sumoyl switches within this SOXB1 motif identified in SOX1, which could regulate its transcriptional activity. This analysis indicates different types of PTMs within SOX1, which may influence its regulatory role as a transcription factor, by bringing changes to its DNA binding capacities and its interactions with partner proteins. These results provide new research avenues for future investigations on the mechanisms regulating SOX1 activity, which could inform its roles in the contexts of neural stem cell development and cancer.
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Miyagi, Satoru, Hidemasa Kato, and Akihiko Okuda. "Role of SoxB1 transcription factors in development." Cellular and Molecular Life Sciences 66, no. 23 (July 25, 2009): 3675–84. http://dx.doi.org/10.1007/s00018-009-0097-0.
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Shih, Y. H., C. L. Kuo, C. S. Hirst, C. T. Dee, Y. R. Liu, Z. A. Laghari, and P. J. Scotting. "SoxB1 transcription factors restrict organizer gene expression by repressing multiple events downstream of Wnt signalling." Development 137, no. 16 (July 7, 2010): 2671–81. http://dx.doi.org/10.1242/dev.054130.
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Milivojevic, Milena, Gordana Nikcevic, Natasa Kovacevic-Grujicic, A. Krstic, Marija Mojsin, Danijela Drakulic, and Milena Stevanovic. "Involvement of ubiquitous and tale transcription factors, as well as liganded RXRα, in the regulation of human SOX2 gene expression in the NT2/D1 embryonal carcinoma cell line." Archives of Biological Sciences 62, no. 2 (2010): 199–210. http://dx.doi.org/10.2298/abs1002199m.
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SOX2 is a key transcription factor in embryonic development representing a universal marker of pluripotent stem cells. Based on the functional redundancy and overlapping expression patterns of SOXB1 subgroup members during development, the goal of this study has been to analyze if some aspects of regulation of expression are preserved between human SOX2 and SOX3 genes. Thus, we have tested several transcription factors previously demonstrated to play roles in controlling SOX3 gene activity for potential participation in the regulation of SOX2 gene expression in NT2/D1 cells. Here we report on the activation of SOX2 expression by ubiquitous transcription factors (NF-Y, Sp1 and MAZ), TALE family members (Pbx1 and Meis1), as well as liganded RXR?. Elucidating components involved in the regulation of SOX gene expression represent a valuable contribution in unraveling the regulatory networks operating in pluripotent embryonic cells.
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Holmberg, J., E. Hansson, M. Malewicz, M. Sandberg, T. Perlmann, U. Lendahl, and J. Muhr. "SoxB1 transcription factors and Notch signaling use distinct mechanisms to regulate proneural gene function and neural progenitor differentiation." Development 135, no. 10 (April 9, 2008): 1843–51. http://dx.doi.org/10.1242/dev.020180.
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Kuo, Cheng-Liang, Chi Man Lam, Jane E. Hewitt, and Paul J. Scotting. "Formation of the Embryonic Organizer Is Restricted by the Competitive Influences of Fgf Signaling and the SoxB1 Transcription Factors." PLoS ONE 8, no. 2 (February 28, 2013): e57698. http://dx.doi.org/10.1371/journal.pone.0057698.
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Buitrago-Delgado, Elsy, Elizabeth N. Schock, Kara Nordin, and Carole LaBonne. "A transition from SoxB1 to SoxE transcription factors is essential for progression from pluripotent blastula cells to neural crest cells." Developmental Biology 444, no. 2 (December 2018): 50–61. http://dx.doi.org/10.1016/j.ydbio.2018.08.008.
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Diks, Sander H., Robert J. Bink, Sandra van de Water, Jos Joore, Carina van Rooijen, Fons J. Verbeek, Jeroen den Hertog, Maikel P. Peppelenbosch, and Danica Zivkovic. "The novel gene asb11: a regulator of the size of the neural progenitor compartment." Journal of Cell Biology 174, no. 4 (August 7, 2006): 581–92. http://dx.doi.org/10.1083/jcb.200601081.
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From a differential display designed to isolate genes that are down-regulated upon differentiation of the central nervous system in Danio rerio embryos, we isolated d-asb11 (ankyrin repeat and suppressor of cytokine signaling box–containing protein 11). Knockdown of the d-Asb11 protein altered the expression of neural precursor genes sox2 and sox3 and resulted in an initial relative increase in proneural cell numbers. This was reflected by neurogenin1 expansion followed by premature neuronal differentiation, as demonstrated by HuC labeling and resulting in reduced size of the definitive neuronal compartment. Forced misexpression of d-asb11 was capable of ectopically inducing sox2 while it diminished or entirely abolished neurogenesis. Overexpression of d-Asb11 in both a pluripotent and a neural-committed progenitor cell line resulted in the stimulus-induced inhibition of terminal neuronal differentiation and enhanced proliferation. We conclude that d-Asb11 is a novel regulator of the neuronal progenitor compartment size by maintaining the neural precursors in the proliferating undifferentiated state possibly through the control of SoxB1 transcription factors.
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Kim, Hee-Dae, Han Kyoung Choe, Sooyoung Chung, Myungjin Kim, Jae Young Seong, Gi Hoon Son, and Kyungjin Kim. "Class-C SOX Transcription Factors Control GnRH Gene Expression via the Intronic Transcriptional Enhancer." Molecular Endocrinology 25, no. 7 (July 1, 2011): 1184–96. http://dx.doi.org/10.1210/me.2010-0332.
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Abstract GnRH is a pivotal hypothalamic neurohormone governing reproduction and sexual development. Because transcriptional regulation is crucial for the spatial and temporal expression of the GnRH gene, a region approximately 3.0 kb upstream of the mammalian GnRH promoter has been extensive studied. In the present study, we demonstrate a transcription-enhancer located in the first intron (intron A) region of the GnRH gene. This transcriptional enhancer harbors putative sex-determining region Y-related high-mobility-group box (SOX) family transcription factor-binding sites, which are well conserved across many mammalian species. The class-C SOX member proteins (SOX-C) (SOX4 and SOX11) specifically augment this transcriptional activation by binding to these SOX-binding sites. In accordance, SOX11 is highly enriched in immortalized GnRH-producing GT1-1 cells, and suppression of its expression significantly decreases GnRH gene expression as well as GnRH secretion. Chromatin immunoprecipitation shows that endogenous SOX-C factors recognize and bind to the intronic enhancer in GT1-1 cells and the hypothalamus. Accompanying immunohistochemical analysis demonstrates that SOX4 or SOX11 are highly expressed in the majority of hypothalamic GnRH neurons in adult mice. Taken together, these findings demonstrate that SOX-C transcription factors function as important transcriptional regulators of cell type-specific GnRH gene expression by acting on the intronic transcriptional enhancer.
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Tanaka, Shinya, Yusuke Kamachi, Aki Tanouchi, Hiroshi Hamada, Naihe Jing, and Hisato Kondoh. "Interplay of SOX and POU Factors in Regulation of the Nestin Gene in Neural Primordial Cells." Molecular and Cellular Biology 24, no. 20 (October 15, 2004): 8834–46. http://dx.doi.org/10.1128/mcb.24.20.8834-8846.2004.
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ABSTRACT Intermediate-filament Nestin and group B1 SOX transcription factors (SOX1/2/3) are often employed as markers for neural primordium, suggesting their regulatory link. We have identified adjacent and essential SOX and POU factor binding sites in the Nestin neural enhancer. The 30-bp sequence of the enhancer including these sites (Nes30) showed a nervous system-specific and SOX-POU-dependent enhancer activity in multimeric forms in transfection assays and was utilized in assessing the specificity of the synergism; combinations of either group B1 or group C SOX (SOX11) with class III POU proved effective. In embryonic day 13.5 mouse spinal cord, Nestin was expressed in the cells with nuclei in the ventricular and subventricular zones. SOX1/2/3 expression was confined to the nuclei of the ventricular zone; SOX11 localized to the nuclei of both subventricular (high-level expression) and intermediate (low-level expression) zones. Class III POU (Brn2) was expressed at high levels, localizing to the nucleus in the ventricular and subventricular zones; moderate expression was observed in the intermediate zone, distributed in the cytoplasm. These data support the model that synergic interactions between group B1/C SOX and class III POU within the nucleus determine Nestin expression. Evidence also suggests that such interactions are involved in the regulation of neural primordial cells.
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Hett, Anne Kathrin, and Arne Ludwig. "SRY-related (Sox) genes in the genome of European Atlantic sturgeon (Acipenser sturio)." Genome 48, no. 2 (April 1, 2005): 181–86. http://dx.doi.org/10.1139/g04-112.
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The Sox-gene family represents an ancient group of transcription factors involved in numerous developmental processes and sex determination in vertebrates. SOX proteins are characterized by a conserved high mobility group (HMG)-box domain, which is responsible for DNA binding and bending. We studied Sox genes in sturgeon, one of the most primitive groups of fishes characterized by a high chromosome number. Male and female genomes were screened for Sox genes using highly degenerate primers that amplified a broad range of HMG boxes. A total of 102 clones, representing 22 different sequences coding for 8 Sox genes, was detected and classified according to their orthologues. Sox2, Sox3, Sox4, Sox9, Sox11, Sox17, Sox19, and Sox21 were found in sturgeon; these genes represent Sox groups B, C, E, and F. In a phylogenetic analysis (neighbor-joining, maximum likelihood, maximum parsimony), these genes clustered with their mouse orthologues. In the case of Sox4, Sox17, and Sox21, we found evidence of gene duplication.Key words: Acipenseridae, gene evolution, sex determination, Sox genes.
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Hoser, Melanie, Michaela R. Potzner, Julia M. C. Koch, Michael R. Bösl, Michael Wegner, and Elisabeth Sock. "Sox12 Deletion in the Mouse Reveals Nonreciprocal Redundancy with the Related Sox4 and Sox11 Transcription Factors." Molecular and Cellular Biology 28, no. 15 (May 27, 2008): 4675–87. http://dx.doi.org/10.1128/mcb.00338-08.
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ABSTRACT The transcription factors Sox4 and Sox11 are important regulators of diverse developmental processes including heart, lung, pancreas, spleen, and B-cell development. Here we have studied the role of the related Sox12 as the third protein of the SoxC group both in vivo and in vitro. Despite widespread Sox12 expression during embryonic development, Sox12-deficient mice developed surprisingly normally, so that they were born alive, showed no gross phenotypic abnormalities, and were fertile in both sexes. Comparison with the related Sox4 and Sox11 revealed extensive overlap in the embryonic expression pattern but more uniform expression levels for Sox12, without sites of particularly high expression. All three Sox proteins furthermore exhibited comparable DNA-binding characteristics and functioned as transcriptional activators. Sox12 was, however, a relatively weak transactivator in comparison to Sox11. We conclude that Sox4 and Sox11 function redundantly with Sox12 and can compensate its loss during mouse development. Because of differences in expression levels and transactivation rates, however, functional compensation is not reciprocal.
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von Wittgenstein, Julia, Fang Zheng, Marie-Theres Wittmann, Elli-Anna Balta, Fulvia Ferrazzi, Iris Schäffner, Benjamin M. Häberle, et al. "Sox11 is an Activity-Regulated Gene with Dentate-Gyrus-Specific Expression Upon General Neural Activation." Cerebral Cortex 30, no. 6 (February 20, 2020): 3731–43. http://dx.doi.org/10.1093/cercor/bhz338.
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Abstract Neuronal activity initiates transcriptional programs that shape long-term changes in plasticity. Although neuron subtypes differ in their plasticity response, most activity-dependent transcription factors (TFs) are broadly expressed across neuron subtypes and brain regions. Thus, how region- and neuronal subtype-specific plasticity are established on the transcriptional level remains poorly understood. We report that in young adult (i.e., 6–8 weeks old) mice, the developmental TF SOX11 is induced in neurons within 6 h either by electroconvulsive stimulation or by exploration of a novel environment. Strikingly, SOX11 induction was restricted to the dentate gyrus (DG) of the hippocampus. In the novel environment paradigm, SOX11 was observed in a subset of c-FOS expressing neurons (ca. 15%); whereas around 75% of SOX11+ DG granule neurons were c-FOS+, indicating that SOX11 was induced in an activity-dependent fashion in a subset of neurons. Environmental enrichment or virus-mediated overexpression of SOX11 enhanced the excitability of DG granule cells and downregulated the expression of different potassium channel subunits, whereas conditional Sox11/4 knock-out mice presented the opposite phenotype. We propose that Sox11 is regulated in an activity-dependent fashion, which is specific to the DG, and speculate that activity-dependent Sox11 expression may participate in the modulation of DG neuron plasticity.
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Yang, Zhi, Shuai Jiang, Chenxi Lu, Ting Ji, Wenwen Yang, Tian Li, Jianjun Lv, Wei Hu, Yang Yang, and Zhenxiao Jin. "SOX11: friend or foe in tumor prevention and carcinogenesis?" Therapeutic Advances in Medical Oncology 11 (January 2019): 175883591985344. http://dx.doi.org/10.1177/1758835919853449.
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Sex-determining region Y-related high-mobility-group box transcription factor 11 (SOX11) is an essential member of the SOX transcription factors and has been highlighted as an important regulator in embryogenesis. SOX11 studies have only recently shifted focus from its role in embryogenesis and development to its function in disease. In particular, the role of SOX11 in carcinogenesis has become of major interest in the field. SOX11 expression is elevated in a wide variety of tumors. In many cancers, dysfunctional expression of SOX11 has been correlated with increased cancer cell survival, inhibited cell differentiation, and tumor progression through the induction of metastasis and angiogenesis. Nevertheless, in a limited number of malignancies, SOX11 has also been identified to function as a tumor suppressor. Herein, we review the correlation between the expression of SOX11 and tumor behaviors. We also summarize the mechanisms underlying the regulation of SOX11 expression and activity in pathological conditions. In particular, we focus on the pathological processes of cancer targeted by SOX11 and discuss whether SOX11 is protective or detrimental during tumor progression. Moreover, SOX11 is highlighted as a clinical biomarker for the diagnosis and prognosis of various human cancer. The information reviewed here should assist in future experimental designs and emphasize the potential of SOX11 as a therapeutic target for cancer.
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Kuo, Pei-Yu, Violetta V. Leshchenko, Tobias A. Gellen, Netha Ulahannan, Paul Zumbo, Christopher E. Mason, Wyndham H. Wilson, et al. "High-Resolution Chromatin Immunoprecipitation (ChIP) Sequencing Identifies Novel Binding Targets and Prognostic Role for SOX11 in Mantle Cell Lymphoma." Blood 118, no. 21 (November 18, 2011): 585. http://dx.doi.org/10.1182/blood.v118.21.585.585.
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Abstract Abstract 585 SOX11 belongs to the high-mobility group of transcription factors that bind to DNA and induce large conformational changes that facilitate the binding of other transcription factors. Genome-wide methylation analysis of Mantle cell lymphoma (MCL) patients using Nimblegen arrays identified SOX11 as hypomethylated and overexpressed in comparison to purified naïve B cells, which are the cells from which MCLs originate. Direct sequencing of SOX11 in MCL cell lines and patient samples failed to identify any activating mutations in SOX11, strengthening the role of aberrant promoter hypomethylation in MCL as the cause of its overexpression. SOX11 expression has been previously compared between Non-Hodgkin's lymphomas and found to be specific for MCL. The function and direct binding targets of SOX11 are unknown. To understand the functional role of SOX11 in MCL, we used high-resolution whole-genome chromatin immunoprecipitation sequencing (ChIP-Seq) to identify the target genes directly bound by SOX11. As a model, genomic DNA from the Granta-519 MCL cell line was immunoprecipitated by SOX11 antibody and IgG and genomic enrichment sites were analyzed by Illumina sequencing. Using stringent statistical criteria (p-value<0.01, fold change≥1.5, and FDR<0.01) we identified 5682 peak positions with significant enrichment of ChIP sequencing reads corresponding to 888 unique genes. Sequencing runs from independent immunoprecipitates had more than 95% overlap in binding targets. These targets were filtered with published gene sets of differentially expressed genes following SOX11 overexpression in MCL cell lines. Pathway analysis revealed cell cycle, FOXm transcriptional network, and TGF-beta receptor signaling as the top three significantly enriched pathways by SOX11 target genes. All three pathways prominently consist of genes with anti-proliferative effects in MCL and B-NHL in general. To test our hypothesis, we transfected SOX11 by lentiviral plasmids into four MCL cell lines with varying levels of intrinsic SOX11 expression. Overexpression of SOX11 led to decreased proliferation in all four cell lines as measured by long-term tracing of living cells using a fluorescent labeled dye to track cell division. Ingenuity Pathway Analysis also identified the tumor promoting Wnt, PKC and IGFR pathways as being significantly enriched by the binding targets. We validated direct binding of SOX11 to RB1, Wnt4 and PKCA by quantitive PCR of ChIP products from Granta-519 cells. RB1 is a key regulator of entry into cell division tumor suppressor in MCL whereas Wnt signaling activates c-myc, which is oncogenic in MCL. Previously published studies have indicated a significant negative prognostic impact of SOX11 expression on overall survival in MCL. We therefore analyzed SOX11 expression in two large independent tissue microarrays from University of Wisconsin (UW) and British Columbia Cancer Agency (BCCA), respectively. MCL patient samples were scored by experienced hematopathologists. High SOX11 expression was associated with better survival: 41 months for SOX11 positive vs. 11 months for SOX11 negative, (p=0.05) in 58 patients in the UW dataset, however the larger BCCA dataset of 140 patients did not show any statistically significant impact of SOX11 expression on survival (p=0.15). These findings suggest that the prognostic impact of SOX11 is heterogenous, and a subset of patients with high SOX11 expression may have improved survival. In conclusion, high-resolution ChIP-Seq identifies more than 800 novel SOX11 direct binding targets. Differential activation of the diverse biological pathways affected by SOX11 target genes may help explain the differential impact of SOX11 expression on patient outcomes. Disclosures: No relevant conflicts of interest to declare.
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Turan, Soeren, Tom Boerstler, Atria Kavyanifar, Sandra Loskarn, André Reis, Beate Winner, and Dieter Chichung Lie. "A novel human stem cell model for Coffin–Siris syndrome-like syndrome reveals the importance of SOX11 dosage for neuronal differentiation and survival." Human Molecular Genetics 28, no. 15 (April 29, 2019): 2589–99. http://dx.doi.org/10.1093/hmg/ddz089.
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AbstractThe SOXC transcription factors Sox4, Sox11 and Sox12, are critical neurodevelopmental regulators that are thought to function in a highly redundant fashion. Surprisingly, heterozygous missense mutations or deletions of SOX11 were recently detected in patients with Coffin–Siris syndrome-like syndrome (CSSLS), a neurodevelopmental disorder associated with intellectual disability, demonstrating that in humans SOX11 haploinsufficiency cannot be compensated and raising the question of the function of SOX11 in human neurodevelopment. Here, we describe the generation of SOX11+/− heterozygous human embryonic stem cell (hESC) lines by CRISPR/Cas9 genome engineering. SOX11 haploinsufficiency impaired the generation of neurons and resulted in a proliferation/differentiation imbalance of neural precursor cells and enhanced neuronal cell death. Using the SOX11+/− hESC model we provide for the first time experimental evidence that SOX11 haploinsufficiency is sufficient to impair key processes of human neurodevelopment, giving a first insight into the pathophysiology of CSSLS and SOX11 function in human neurodevelopment.
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Williams, Michael E., Sarah Rutherford, Yunjia Tang, and John Cousar. "Nuclear Expression of the Sox 11 Transcription Factor in Mantle Cell Lymphoma, and Cytoplasmic Expression in Follicular Lymphoma and Multiple Myeloma: Pathogenetic Implications." Blood 114, no. 22 (November 20, 2009): 2925. http://dx.doi.org/10.1182/blood.v114.22.2925.2925.
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Abstract Abstract 2925 Poster Board II-901 Mantle cell lymphoma (MCL) is characterized by nuclear cyclin D1 expression resulting from the t(11;14)(q13;q32). As cyclin D1 overexpression alone is insufficient for B-cell transformation, we have investigated other potentially contributing mutations. Sox11 is a member of a large family of transcription factors containing a DNA-binding high-mobility group (HMG) domain and shares homology with Sox4, which is involved in lymphopoiesis. Recent reports have identified Sox11 expression in the majority of MCL, suggesting it may contribute to pathogenesis (Ek et al, Blood 2008;111:800; Wang et al, Br J Haematol 2008;143:248). Methods: Patients with MCL diagnosed at the Univ. of Virginia from 1997-2008 and for whom nodal, marrow or spleen tissue blocks were available were identified from the Pathology database. Follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), hairy cell leukemia (HCL) and multiple myeloma (MM) were also analyzed. Formalin-fixed, paraffin-embedded samples were stained by immunohistochemistry for cyclinD1, Sox11 (rabbit a/Sox11, 1:100, Sigma) and Ki-67. Nuclear and/or cytoplasmic expression was determined by two of us (YT, JC). Results: All MCL samples revealed nuclear cyclin D1 expression. Nuclear but not cytoplasmic Sox11 expression was identified in all 24 non-blastoid and in 5/6 blastoid samples; 1 blastoid sample showed only cytoplasmic Sox11 staining (Table). Four of 5 HCL expressed cyclin D1 but were negative for Sox11; 4/5 MM also were cyclin D1-positive, with 3 positive for cytoplasmic Sox11 including 2 of the cyclin D1-positive cases. All 5 FL showed cytoplasmic Sox11 positivity, whereas all MZL and SLL were negative for cytoplasmic or nuclear staining. Conclusions: Nuclear Sox11 expression was uniformly identified in MCL, with the exception of cytoplasmic expression in a single blastoid case. No nuclear Sox11 was present in HCL or MM despite the expression of cyclin D1, although 3 MM showed cytoplasmic Sox11 staining. These findings suggest that nuclear Sox11 overexpression is not a direct result of dysregulated cyclin D1 signaling but instead occurs by alternative mechanisms. The significance of cytoplasmic staining remains uncertain. A potential pathogenetic role for Sox11 and possibly other Sox family transcription factors warrants further investigation in MCL and other lymphoproliferative neoplasms for diagnostic use and therapeutic targeting. Disclosures: No relevant conflicts of interest to declare.
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Wästerlid, Tove, Lena Nordström, Mette Pedersen, Peter H. Norgaard, Anne Ortved Gang, Peter de Nully Brown, Mats Jerkeman, and Sara Ek. "Frequency and Clinical Implication of SOX11 Expression in Burkitt Lymphoma." Blood 126, no. 23 (December 3, 2015): 5039. http://dx.doi.org/10.1182/blood.v126.23.5039.5039.
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Abstract Introduction: The transcription factor SOX11 is normally expressed during embryogenesis in humans. Several studies have shown that SOX11 is aberrantly expressed in various types of haematopoetic and solid malignancies, and appears to affect clinicopathological characteristics. For example, in mantle cell lymphoma, SOX11 serves as a diagnostic antigen and has been shown to be associated with superior outcome (Nordström et al. British Journal of Haematology 2014), although its role as a prognostic indicator remains controversial. In chronic lymphocytic leukemia, SOX11 was associated with inferior overall survival (Roisman et al. Tumor Biol 2015), whereas SOX11 expression correlated with superior outcome in epithelial ovarian cancer (Sernbo et al. BMC Cancer 2011). Various possible target genes and transcriptional programs have been identified, by which SOX11 may exert both repressive, and exaggerative, functions on proliferation, and potentially function as therapeutic targets in the future (Kuo et al. Oncogene 2015, Vegliante et al. Blood 2013). In Burkitt lymphoma (BL), two small series have reported expression of SOX11 in 30-50 % of cases (Mozos et al. Haematologica 2009, Dictor et al. Haematologica 2009). As of yet, no study has been performed specifically to evaluate the implication of SOX11 expression in BL. The aim of this study was to investigate the frequency of SOX11 positive BL cases in a joint cohort from Denmark and Sweden, and correlate its expression to clinical and pathological parameters. Methods: 45 BL cases were collected from Sweden and Denmark. Samples were analysed for expression of SOX11 and other immunohistochemical markers. Cases were classified classic BL or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU) after pathology review. Clinical data were obtained from the Danish Lymphoma Database (LYFO) and the Swedish Lymphoma Registry. Additionally, 9 pediatric BL cases were analyzed for SOX11 expression, but with no clinical data available. Results: In the adult BL study population 14/45 (31 %) expressed nuclear staining of SOX11. The SOX11 positive subgroup had a higher median age (53 compared to 41), as well as a larger proportion with elevated LDH. Other prognostic factors were equally distributed between the groups. Although a similar proportion of patients received high-intensive chemotherapy in both subgroups, 3 (21 %) received no treatment in the SOX11 positive cohort. In this BL material, 28 (62 %) were classified classic BL and 17 (38 %) BCLU. There was a significant difference in SOX11 expression between classic BL and BCLU (p=0.03). Among classic BL SOX11 was seen in 12/28 (43 %) whereas in BCLU only 2/17 (12 %) expressed SOX11. Five-year overall survival (OS) in the SOX11 positive group was 57 %, compared to 77 % in the SOX11 negative cohort. When adjusting for treatment, BCLU and prognostic factors in multivariable analysis, no significant difference in outcome was seen between groups (hazard ratio: 2.5 95 % confidence interval: 0.4-13.9, p=0.3). When restricting analysis to classic BL cases only, there was no remaining difference in median age, and no significant difference in OS between SOX11 positive and negative patients in neither univariable nor multivariable analysis. In the pediatric cohort, 5/9 (56 %) expressed SOX11. Conclusion: SOX11 expression was found in less than half of classic BL, and in a small minority of BCLU. In contrast to SOX11 expression in other malignancies, SOX11 expression had no significant impact on outcome, in our cohort, when adjusting for prognostic factors, treatment and BCLU. Disclosures Brown: Bayer: Consultancy; Roche: Consultancy, Speakers Bureau.
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Zhao, Suling, Jennifer Nichols, Austin G. Smith, and Meng Li. "SoxB transcription factors specify neuroectodermal lineage choice in ES cells." Molecular and Cellular Neuroscience 27, no. 3 (November 2004): 332–42. http://dx.doi.org/10.1016/j.mcn.2004.08.002.
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Iqbal, Mohd S., Ken-ichiro Otsuyama, Karim Shamsasenjan, and Michio M. Kawano. "Molecular Mechanism of CD56 Expression in Human Myeloma Cells." Blood 112, no. 11 (November 16, 2008): 5130. http://dx.doi.org/10.1182/blood.v112.11.5130.5130.
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Abstract CD56 (NCAM1), one of the non-B cell lineage markers, is frequently detected on primary myeloma cells from more than 80% patients with overt myeloma. Microarray analysis of the CD56(+) myeloma cell lines showed markedly increased expressions of transcription factors involved in the neuronal cell lineage compared to the CD56(−) myeloma cell lines. There are three important binding sites of transcription factors such as HOX, SOX and PAX, present in the CD56 promoter region. Furthermore, ChIP analysis showed the specific bindings of HOXB9 and SOX1 in the CD56 promoter region of both the CD56(+) and CD56(−) myeloma cell line, while there was no significant difference observed in the PAX8 expression between the CD56(+) and CD56(−) myeloma cell lines. RT-PCR and western blot analysis confirmed that HOXB3 and HOXB9 as well as some of their potential cofactors were up-regulated in the CD56(+) myeloma cell lines with the concomitant down-regulation of the SOX1 and OCT3/4. First, we focused on the role of down-regulation of SOX1 in the CD56(−) myeloma cell line by the shRNA transfection. However, shRNA against SOX1 failed to induce CD56 expression in CD56(−) myeloma cell line. Therefore, these results indicate that the down-regulation of SOX1 alone may not be enough for the CD56 induction which might also require the overexpression of either HOXB9 or HOXB3, and the further study in the molecular mechanism of CD56 expression might contribute to the understanding of complex network of the interaction of transcription factors in human myeloma cells.
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Palomero, Jara, Maria Carmela Vegliante, Marta Rodríguez, Ester Planas, Inmaculada Ribera, Maria Cinta Cid, Elias Campo, and Virginia Amador. "SOX11 Regulates Angiogenesis In Mantle Cell Lymphoma." Blood 122, no. 21 (November 15, 2013): 246. http://dx.doi.org/10.1182/blood.v122.21.246.246.
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Abstract Mantle cell lymphoma (MCL) is an aggressive tumor but recent studies have identified a subtype of this lymphoma with an indolent clinical behavior and long survival of the patients even without chemotherapy that may correspond to a different clinical and biological subtype of the disease. These indolent MCLs differ from conventional MCLs in a particular gene signature that lacks the expression of some transcription factors of the High Mobility Group (HMG). SOX11 is one of the best discriminatory genes between these conventional and indolent MCL tumors. We have recently demonstrated the oncogenic implication of SOX11 expression in the aggressive behavior of MCL as SOX11-knockdown derived tumors display a significant reduction on tumor growth compared to SOX11-control tumors in subcutaneous MCL xenograft experiments (Vegliante MC, Palomero J et al. Blood. 2013; 121:2175-85). To uncover SOX11 regulated genes and transcriptional programs in MCL, we performed an integrative analysis coupling data from human genome-wide promoter analysis by SOX11 ChIP-chip experiments and gene expression profiling (GEP) upon SOX11 silencing in MCL cell lines. In these studies we initially identified the role of SOX11 in blocking the terminal B-cell differentiation by the direct positive regulation of PAX5. However, how SOX11 may enhance tumor growth is still not well known. To further characterize the potential oncogenic mechanisms regulated by SOX11, we have integrated our ChIP-chip data with further analyses including GEP derived from the xenografted SOX11-positive and silenced tumors. The gene ontology term analysis of the genome-wide promoter study revealed “blood vessel development” as one of the most significant biological processes overrepresented among the SOX11-bound genes. Concordantly, a gene set enrichment analysis (GSEA) of the differentially expressed genes in the xenografted tumors showed a significant higher enrichment of gene signatures related to tumor angiogenesis in the SOX11-positive tumors. To validate these results in vivo, we first investigated protein extracts of these tumors using an angiogenesis proteome profiler antibody array and discovered a significant higher expression of 20 pro-angiogenic factors in the SOX11-positive tumors. We have then investigated the angiogenic development in tissue sections from four Z-138 SOX11-positive and nine SOX11-silenced xenografted tumors. The microvascular density area recognized by CD31 staining was significantly larger in SOX11-positive than knockdown tumors (90%±µ2m vs 15%±µ2m, respectively, p<1x10-4). SOX11-silenced tumors had larger necrotic areas than positive tumors (20%±µ2m vs 1%±µ2m, respectively, p<1x10-4), suggesting that vascular paucity could contribute to the significant smaller volume of these tumors. To determine whether angiogenic development was also differentially represented in primary human MCL we have studied the GEP of 16 SOX11-positive and 22 SOX11-negative MCL. A GSEA revealed that SOX11 expressing tumors were enriched in signatures related to tumor vasculature, angiogenesis and vasculature development. Concordantly, the CD34 staining of an independent series of primary SOX11-positive (n=8) and negative (n=9) human MCL showed higher microvascular density in SOX11 expressing tumors (30%±µ2m vs 5%±µ2m, respectively, p<1x10-4). In conclusion, these findings indicate that SOX11 promotes angiogenesis in experimental and primary human MCL and this may be an oncogenic mechanism contributing to the aggressiveness of these tumors. Disclosures: No relevant conflicts of interest to declare.
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Thein, Daniela C., Johannes M. Thalhammer, Anna C. Hartwig, E. Bryan Crenshaw III, Veronique Lefebvre, Michael Wegner, and Elisabeth Sock. "The closely related transcription factors Sox4 and Sox11 function as survival factors during spinal cord development." Journal of Neurochemistry 115, no. 1 (August 3, 2010): 131–41. http://dx.doi.org/10.1111/j.1471-4159.2010.06910.x.
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Pevny, L. H., S. Sockanathan, M. Placzek, and R. Lovell-Badge. "A role for SOX1 in neural determination." Development 125, no. 10 (May 15, 1998): 1967–78. http://dx.doi.org/10.1242/dev.125.10.1967.
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In vertebrates, the delineation of the neural plate from a region of the primitive ectoderm is accompanied by the onset of specific gene expression which in turn promotes the formation of the nervous system. Here we show that SOX1, an HMG-box protein related to SRY, is one of the earliest transcription factors to be expressed in ectodermal cells committed to the neural fate: the onset of expression of SOX1 appears to coincide with the induction of neural ectoderm. We demonstrate a role for SOX1 in neural determination and differentiation using an inducible expression P19 cell system as an in vitro model of neurogenesis. Misexpression of SOX1 can substitute for the requirement of retinoic acid to impart neural fate to competent ectodermal P19 cells. Using a series of antigenic markers which identify early neural cell types in combination with BrdU labeling, we demonstrate a temporal and spatial correlation between the differentiation of cell types along the dorsoventral axis of the neural tube and the downregulation of SOX1 expression. SOX1, therefore, defines the dividing neural precursors of the embryonic central nervous system (CNS).
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Gnedeva, Ksenia, and A. J. Hudspeth. "SoxC transcription factors are essential for the development of the inner ear." Proceedings of the National Academy of Sciences 112, no. 45 (October 26, 2015): 14066–71. http://dx.doi.org/10.1073/pnas.1517371112.
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Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance.
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Christie, Stephanie, Shashidhar Jatiani, Pei-Yu Kuo, Violetta Leshchenko, Abhijeet Kapoor, Paola Bisignano, Aneel Aggarwal, Marta Filizola, and Samir Parekh. "Inhibiting SOX11-DNA Interaction in Mantle Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 1840. http://dx.doi.org/10.1182/blood.v128.22.1840.1840.
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Abstract Mantle Cell Lymphoma (MCL) is a fatal subtype of Non-Hodgkins Lymphoma. MCL is characterized by cell cycle dysregulation due to Cyclin D1 (CCND1) overexpression. Murine models overexpressing CCND1 do not develop B-cell proliferation. The SOX11 transcription factor is overexpressed in the majority of nodal human MCL and has been implicated in MCL pathogenesis. We have developed a transgenic Eµ-SOX11-EGFP mouse model that overexpresses SOX11 with aberrant B cell proliferation, lymphadenopathy, spenomegaly and hepatomegaly phenocopying the characteristics of patients with MCL. Using Mass Cytometry (CyTOF), we further characterized this B cell population to be CD23-, CD21/35 dim, CD138-, high surface IgM, and variable IgD expression, an immunophenotype identical to human MCL. SOX11 overexpression drives B cell receptor (BCR) signaling in murine MCL cells, assayed by phosphorylation of p-BTK and p-PLC gamma. To further the study of the role of SOX11 in MCL, compounds inhibiting the binding interaction of SOX11 and DNA are highly desirable and we aim at their discovery by using structure-based virtual screening predictions and experimental validations. No small-molecule inhibitor of SOX11-DNA binding has been developed to date and there is an unmet need in MCL therapeutics for novel and successful treatments. Transcription factors have been considered "undruggable" but since SOX11 binds the minor groove in DNA, we hypothesized that there may be pockets created by SOX11-DNA binding that could be inhibited by small molecules. We therefore built a human SOX11 homology model using the crystal structure of murine SOX4 (98% homology). We first docked molecules from the NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC). From this virtual screening, 70 compounds were purchased for experimental testing. Using a fluorescence anisotropy assay, Flavitan was identified as a potential inhibitor of the SOX11-DNA interaction. Based on inferences from the predicted binding mode of Flavitan on SOX11, we performed another virtual screening of ~12 million molecules from the ZINC database followed by assaying 26 top-scoring compounds, as well as, 16 derivatives of one of them, for SOX11 binding. We thus discovered two compounds, R and T, with binding constants in the low micromolar range. Importantly, compounds R and T were found not to intercalate DNA in a Topoisomerase I based assay. To assess the biological activity of these molecules, we tested whether BCR signaling in MCL cell lines expressing SOX11 would be inhibited by treatment with these compounds. Compounds R and T significantly inhibited p-BTK as compared to vehicle control. Ibrutinib, an FDA approved BTK inhibitor, was used as a positive control in these experiments. To determine whether BCR pathway inhibition through compounds R and T would be cytotoxic in SOX11 positive MCL cell lines, we treated Z138 and JEKO cells with these small-molecules and assayed Annexin-V and PI staining 48 hours later by flow-cytometry. Our results indicate that compound R has greater single agent cytotoxic activity than compound T and Ibrutinib. Compounds R and T also showed synergistic cytotoxicity in combination with Ibrutinib in SOX11 expressing Z138 and JEKO cells, but not in JVM2, a SOX11 negative MCL cell line. In summary, through a combination of in silico predictions and experimental validation, we have identified small-molecule inhibitors of SOX11-DNA binding as candidate leads for optimization for anti-MCL therapy. Disclosures No relevant conflicts of interest to declare.
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Sander, Birgitta, Monika Klimkowska, Lina Nygren, Stefanie Baumgartner, Birger Christensson, and Eva Kimby. "SOX11 Expression Versus Indolent Clinical Course in Mantle Cell Lymphomas in a Population-Based Cohort From the Stockholm Region – SOX11 Negative Tumors Are Mostly p53 Positive, Contributing to Shorter Overall Survival,." Blood 118, no. 21 (November 18, 2011): 3651. http://dx.doi.org/10.1182/blood.v118.21.3651.3651.
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Abstract Abstract 3651 Introduction: Mantle cell lymphoma (MCL) constitutes 3–10% of non-Hodgkin lymphomas and has a median survival of 3–5 years. A small number of patients are characterized by a clinically indolent disease and may not require treatment for several years. However, these are difficult to identify at the time of diagnosis due to lack of reliable predictive markers. Recently, the nuclear expression of the transcription factor SOX11 has been suggested to be of prognostic value in MCL. Materials and Methods: All 186 patients diagnosed with MCL in the Stockholm region between January 1998 and June 2010 were included. Diagnosis was according to the WHO criteria and all cases were cyclin D1 positive by IHC and/or for t(11;14) by FISH. Clinical data from patient files, diagnostic biopsies and flow cytometry data were reviewed. Patients not requiring treatment within the first two years after diagnosis were retrospectively defined as indolent disease. Patients were further categorized in nuclear SOX11 negative (n=13) and nuclear SOX11 positive (n=160) cases and in cases with indolent (n=17) versus non-indolent disease course (n=169). The following variables were evaluated at the time of diagnosis: age, sex, Ann Arbor stage, ECOG, B-symptoms, Hb, LDH, albumin, lymphocytosis, leukocytosis, splenomegaly, nodal and bone marrow involvement, MIPI, indolent disease, blastoid morphology, expression of CD23, light chain, Ki 67, SOX11 and p53. Overall survival was analyzed, excluding patients receiving ASCT (n=37). Baumgartner, S. et al presents further data on the entire cohort in the accompanying abstract. Results: The following variables were significantly more common in SOX11 negative cases (Table 1): Lymphocytosis (p=0,045), high LDH (p=0,029) and p53 positivity (p<0,000). MIPI high risk was more frequent among SOX11 negative patients but did not reach statistical difference. There were no statistically significant differences in the frequency of splenomegaly or indolent disease among SOX11 negative and positive cases. Median overall survival time was 36,7 months in the whole cohort; 16,5 months in patients with SOX11 negative tumors and 39,3 months in patients with SOX11 positive tumors (p=0,015), excluding 37 patients (1 SOX11 negative, 38 SOX11 positive) receiving ASCT as part of first-line therapy. Patients with an indolent clinical course had significantly less often B symptoms (p=0,002), nodal presentation (p=0,019) and elevated LDH (p=0,040) than patients with a non-indolent disease, while none of the other factors analyzed reached statistical significance. Median overall survival time of patients with indolent disease was not reached (median follow-up time 41,7 months). 15/17 of the MCL cases with indolent clinical course expressed SOX11. Conclusions: In a population-based cohort of 186 cyclin D1 positive MCL, 8% lacked expression of nuclear SOX11 at diagnosis. There was no enrichment of patients with an indolent disease among SOX11 negative MCL. Instead patients with SOX11 negative MCL had a higher frequency of lymphocytosis and elevated LDH at diagnosis and a shorter overall survival. MCL lacking nuclear SOX11 expression at diagnosis were more frequently p53 positive which may contribute to shorter survival in the SOX11 negative MCL subset. Disclosures: No relevant conflicts of interest to declare.
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Jiang, Ying, Qian Ding, Xiaoling Xie, Richard T. Libby, Veronique Lefebvre, and Lin Gan. "Transcription Factors SOX4 and SOX11 Function Redundantly to Regulate the Development of Mouse Retinal Ganglion Cells." Journal of Biological Chemistry 288, no. 25 (May 6, 2013): 18429–38. http://dx.doi.org/10.1074/jbc.m113.478503.
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Beleaua, Marius-Alexandru, Ioan Jung, Cornelia Braicu, Doina Milutin, and Simona Gurzu. "SOX11, SOX10 and MITF Gene Interaction: A Possible Diagnostic Tool in Malignant Melanoma." Life 11, no. 4 (March 27, 2021): 281. http://dx.doi.org/10.3390/life11040281.
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Malignant melanoma (MM) is a highly heterogenic tumor whose histological diagnosis might be difficult. This study aimed to investigate the diagnostic and prognostic utility of the conventional pan-melanoma cocktail members (HMB-45, melan-A and tyrosinase), in conjunction with SOX10 and SOX11 immunohistochemical (IHC) expression. In 105 consecutive cases of MMs and 44 of naevi, the IHC examination was performed using the five-abovementioned markers, along with microphthalmia transcription factor (MITF), S100, and Ki67. Correlation with the clinicopathological factors and a long-term follow-up was also done. Survival analysis was performed with Kaplan–Meier curves and compared with TCGA public datasets. None of the 44 naevi expressed SOX11, but its positivity was seen in 52 MMs (49.52%), being directly correlated with lymphovascular invasion, the Ki67 index, and SOX10 expression. HMB-45, SOX10, and tyrosinase, but not melan-A, proved to differentiate the naevi from MMs successfully, with high specificity. Triple MITF/SOX10/SOX11 co-expression was seen in 9 out of 15 negative conventional pan-melanoma-cocktail cases. The independent prognostic value was proved for the conventional pan-melanoma cocktail (triple positivity for HMB-45, melan-A, and tyrosinase) and, independently for HMB-45 and tyrosinase, but not for melan-A, SOX10, or SOX11. As consequence, to differentiate MMs from benign naevi, melan-A should be substituted by SOX10 in the conventional cocktail. Although the conventional pan-melanoma cocktail, along with S100 can be used for the identification of melanocytic origin of tumor cells and predicting prognosis of MMs, the conventional-adapted cocktail (triple positivity for HMB-45, SOX10, and tyrosinase) has a slightly higher diagnostic specificity. SOX11 can be added to identify the aggressive MMs with risk for lymphatic dissemination and the presence of circulating tumor cells.
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Nishimura, Riko, Kenji Hata, Yoshifumi Takahata, Tomohiko Murakami, Eriko Nakamura, Maki Ohkawa, and Lerdluck Ruengsinpinya. "Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases." International Journal of Molecular Sciences 21, no. 4 (February 17, 2020): 1340. http://dx.doi.org/10.3390/ijms21041340.
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Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.
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Kim, Dong Ki, Seung Baek Han, Soon Taek Hong, Yoo Jean Choi, Woong Sun, Dongho Geum, and Hyun Kim. "Expression of Sox11 and Brn transcription factors during development and following transient forebrain ischemia in the rat." Neuroscience Letters 433, no. 3 (March 2008): 259–64. http://dx.doi.org/10.1016/j.neulet.2008.01.016.
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Das, Debanu, Fumiaki Yumoto, Kristopher Kuchenbecker, Ashley Deacon, Robert Fletterick, and Ian Wilson. "Understanding disease mutations from the crystal structure of SOX9 with DNA." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1398. http://dx.doi.org/10.1107/s205327331408601x.
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SRY(Sex determining Region Y)-box or SOX transcription factors are important in early development and maintenance of different cell pools after birth. Of the ~20 SOX proteins (SRY, SOX1-SOX15, SOX17, SOX18, SOX21 and SOX30), SOX2, SOX9 and SOX10 mutations are primarily disease-associated: SOX2 with Combined Pituitary Hormone Deficiency, Microphthalmia, Septo-optic dysplasia and anophthalmic syndrome; SOX9 with Campomelic Dysplasia (affects development of the reproductive and skeletal system); and SOX10 (~94% sequence identity to SOX9) with Waardenburg Syndrome (affects audition and pigmentation in hair, eyes and skin; and specifically with WS types 2 and 4). As part of our Protein Structure Initiative (PSI)-Biology partnership, we performed structural and mutational analyses including x-ray crystallography and surface plasmon resonance assays, on the DNA-binding HMG domain of SOX9 with duplex DNA. Crystals were obtained in C222 space group and the structure was determined by molecular replacement to 2.77 Å resolution with final Rcryst/Rfree of 24.8/27.8%. The overall structure of the SOX9-DNA complex is similar to other SOX/SRY protein complexes. The SOX9-DNA protein-DNA interactions suggested a panel of mutations to assay for biochemical activity, which allowed us to understand the molecular basis of five mutations identified in Campomelic Dysplasia. These mutated residues have direct contact with DNA as well as indirect contacts, i.e., these mutations lead to allosteric secondary structure changes in the protein, which affect residues in direct contact with DNA. Due to the very high sequence identity between SOX9 and SOX10, our crystal structure also helps to rationalize the effect of SOX10 mutations in Waardenburg Syndrome. This work is supported by NIH grants U54 GM094586 and U01 GM094614. SSRL operations are funded by DOE BES, and the SSRL SMB program by DOE BER, NIH NCRR BTP and NIH NIGMS.
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Potzner, Michaela R., Carola Griffel, Elke Lütjen-Drecoll, Michael R. Bösl, Michael Wegner, and Elisabeth Sock. "Prolonged Sox4 Expression in Oligodendrocytes Interferes with Normal Myelination in the Central Nervous System." Molecular and Cellular Biology 27, no. 15 (May 21, 2007): 5316–26. http://dx.doi.org/10.1128/mcb.00339-07.
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ABSTRACT The highly related transcription factors Sox4 and Sox11 are both expressed in oligodendrocyte precursors. Yet whether they have a function in oligodendrocyte development is unknown. By overexpressing Sox4 under the control of 3.1 kb of 5′ flanking sequences of the myelin basic protein gene in transgenic mice, we extended Sox4 expression in the oligodendrocyte lineage from oligodendrocyte precursors to cells undergoing terminal differentiation. As a consequence of transgene expression, mice develop the full spectrum of phenotypic traits associated with a severe hypomyelination during the first postnatal weeks. Myelin gene expression was severely reduced, and myelin dramatically thinned in several central nervous system (CNS) regions. Despite these disturbances in CNS myelination, the number of oligodendrocytic cells remained unaltered. Considering that apoptosis rates were normal and proliferation only slightly increased, oligodendrocytes likely persist in a premyelinating to early myelinating state. This shows that prolonged Sox4 expression in cells of the oligodendrocyte lineage is incompatible with the acquisition of a fully mature phenotype and argues that the presence of Sox4, and possibly Sox11, in oligodendrocyte precursors may normally prevent premature differentiation.
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Kamachi, Y., M. Uchikawa, J. Collignon, R. Lovell-Badge, and H. Kondoh. "Involvement of Sox1, 2 and 3 in the early and subsequent molecular events of lens induction." Development 125, no. 13 (July 1, 1998): 2521–32. http://dx.doi.org/10.1242/dev.125.13.2521.
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Activation of the first lens-specific gene of the chicken, delta 1-crystallin, is dependent on a group of lens nuclear factors, deltaEF2, interacting with the delta1-crystallin minimal enhancer, DC5. One of the deltaEF2 factors was previously identified as SOX2. We show that two related SOX proteins, SOX1 and SOX3, account for the remaining members of deltaEF2. Activation of the DC5 enhancer is dependent on their C-terminal domains. Expression of Sox1-3 in the eye region during lens induction was studied in comparison with Pax6 and delta1-crystallin. Pax6, known to be required for the inductive response of the ectoderm, is broadly expressed in the lateral head ectoderm from before lens induction. After tight association of the optic vesicle (around stage 10–11, 40 hours after egg incubation), expression of Sox2 and Sox3 is activated in the vesicle-facing ectoderm at stage 12 (44 hours). These cells, expressing together Pax6 and Sox2/3, subsequently give rise to the lens, beginning with formation of the lens placode and expression of delta-crystallin at stage 13 (48 hours). Sox1 then starts to be expessed in the lens-forming cells at stage 14. When the prospective retina area of the neural plate was unilaterally ablated at stage 7, expression of Sox2/3 was lost in the side of lateral head ectoderm lacking the optic cup, implying that an inductive signal from the optic cup activates Sox2/3 expression. In the mouse embryonic lens, this subfamily of Sox genes is expressed in an analogous fashion, although Sox3 transcripts have not been detected and Sox2 expression is down-regulated when Sox1 is activated. In ectodermal tissues of the chicken embryo, delta -crystallin expression occurs in a few ectopic sites. These are always characterized by overlapping expression of Sox2/3 and Pax6. Thus, an essential molecular event in lens induction is the ‘turning on’ of the transcriptional regulators SOX2/3 in the Pax6-expressing ectoderm and these SOX proteins activate crystallin gene expression. Continued activity, especially of SOX1, is then essential for further development of the lens.
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Lamichhaney, Sangeet, Angela P. Fuentes-Pardo, Nima Rafati, Nils Ryman, Gregory R. McCracken, Christina Bourne, Rabindra Singh, Daniel E. Ruzzante, and Leif Andersson. "Parallel adaptive evolution of geographically distant herring populations on both sides of the North Atlantic Ocean." Proceedings of the National Academy of Sciences 114, no. 17 (April 7, 2017): E3452—E3461. http://dx.doi.org/10.1073/pnas.1617728114.
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Atlantic herring is an excellent species for studying the genetic basis of adaptation in geographically distant populations because of its characteristically large population sizes and low genetic drift. In this study we compared whole-genome resequencing data of Atlantic herring populations from both sides of the Atlantic Ocean. An important finding was the very low degree of genetic differentiation among geographically distant populations (fixation index = 0.026), suggesting lack of reproductive isolation across the ocean. This feature of the Atlantic herring facilitates the detection of genetic factors affecting adaptation because of the sharp contrast between loci showing genetic differentiation resulting from natural selection and the low background noise resulting from genetic drift. We show that genetic factors associated with timing of reproduction are shared between genetically distinct and geographically distant populations. The genes for thyroid-stimulating hormone receptor (TSHR), the SOX11 transcription factor (SOX11), calmodulin (CALM), and estrogen receptor 2 (ESR2A), all with a significant role in reproductive biology, were among the loci that showed the most consistent association with spawning time throughout the species range. In fact, the same two SNPs located at the 5′ end of TSHR showed the most significant association with spawning time in both the east and west Atlantic. We also identified unexpected haplotype sharing between spring-spawning oceanic herring and autumn-spawning populations across the Atlantic Ocean and the Baltic Sea. The genomic regions showing this pattern are unlikely to control spawning time but may be involved in adaptation to ecological factor(s) shared among these populations.
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Buescher, Marita, Fook Sion Hing, and William Chia. "Formation of neuroblasts in the embryonic central nervous system of Drosophila melanogaster is controlled by SoxNeuro." Development 129, no. 18 (September 15, 2002): 4193–203. http://dx.doi.org/10.1242/dev.129.18.4193.
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Sox proteins form a family of HMG-box transcription factors related to the mammalian testis determining factor SRY. Sox-mediated modulation of gene expression plays an important role in various developmental contexts. Drosophila SoxNeuro, a putative ortholog of the vertebrate Sox1, Sox2 and Sox3 proteins, is one of the earliest transcription factors to be expressed pan-neuroectodermally. We demonstrate that SoxNeuro is essential for the formation of the neural progenitor cells in central nervous system. We show that loss of function mutations of SoxNeuro are associated with a spatially restricted hypoplasia: neuroblast formation is severely affected in the lateral and intermediate regions of the central nervous system, whereas ventral neuroblast formation is almost normal. We present evidence that a requirement for SoxNeuro in ventral neuroblast formation is masked by a functional redundancy with Dichaete, a second Sox protein whose expression partially overlaps that of SoxNeuro. Genetic interactions of SoxNeuro and the dorsoventral patterning genes ventral nerve chord defective and intermediate neuroblasts defective underlie ventral and intermediate neuroblast formation. Finally, the expression of the Achaete-Scute gene complex suggests that SoxNeuro acts upstream and in parallel with the proneural genes.
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Tenorio-Mina, Andrea, Daniel Cortés, Joel Esquivel-Estudillo, Adolfo López-Ornelas, Alejandro Cabrera-Wrooman, Rolando Lara-Rodarte, Itzel Escobedo-Avila, et al. "Human Keratinocytes Adopt Neuronal Fates After In Utero Transplantation in the Developing Rat Brain." Cell Transplantation 30 (January 1, 2021): 096368972097821. http://dx.doi.org/10.1177/0963689720978219.
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Human skin contains keratinocytes in the epidermis. Such cells share their ectodermal origin with the central nervous system (CNS). Recent studies have demonstrated that terminally differentiated somatic cells can adopt a pluripotent state, or can directly convert its phenotype to neurons, after ectopic expression of transcription factors. In this article we tested the hypothesis that human keratinocytes can adopt neural fates after culturing them in suspension with a neural medium. Initially, keratinocytes expressed Keratins and Vimentin. After neural induction, transcriptional upregulation of NESTIN, SOX2, VIMENTIN, SOX1, and MUSASHI1 was observed, concomitant with significant increases in NESTIN detected by immunostaining. However, in vitro differentiation did not yield the expression of neuronal or astrocytic markers. We tested the differentiation potential of control and neural-induced keratinocytes by grafting them in the developing CNS of rats, through ultrasound-guided injection. For this purpose, keratinocytes were transduced with lentivirus that contained the coding sequence of green fluorescent protein. Cell sorting was employed to select cells with high fluorescence. Unexpectedly, 4 days after grafting these cells in the ventricles, both control and neural-induced cells expressed green fluorescent protein together with the neuronal proteins βIII-Tubulin and Microtubule-Associated Protein 2. These results support the notion that in vivo environment provides appropriate signals to evaluate the neuronal differentiation potential of keratinocytes or other non-neural cell populations.
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Gerber, Vanessa, Lixin Yang, Masanari Takamiya, Vanessa Ribes, Victor Gourain, Ravindra Peravali, Johannes Stegmaier, et al. "The HMG box transcription factors Sox1a and Sox1b specify a new class of glycinergic interneuron in the spinal cord of zebrafish embryos." Development 146, no. 4 (February 13, 2019): dev172510. http://dx.doi.org/10.1242/dev.172510.
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Hu, Guangzhen, Asha Nair, Tammy Price-Troska, Eric D. Wieben, and Mamta Gupta. "Mantle Cell Lymphoma Associated Long Non-Coding RNAs Regulate Polycomb Repressive Complex-2." Blood 124, no. 21 (December 6, 2014): 140. http://dx.doi.org/10.1182/blood.v124.21.140.140.
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Abstract Long non-coding RNAs (lncRNA) are key regulatory RNAs that do not code for protein. Recently lncRNAs have been recognized as key regulators of gene expression and chromatin organization. Although, deregulation of lncRNAs such as HOTAIR, MALAT1 and H19 has been reported in solid cancers, role of lncRNAs in lymphoma or other hematologic malignancies is not known. The aim of this study is to identify lymphoma-associated lncRNAs and elucidate their role in disease pathogenesis. Next generation RNA-sequencing and validation studies were carried out on mantle cell lymphoma (MCL) patient samples along with normal controls. As a result, hundreds of lncRNAs were found overexpressed in the MCL samples as compared with normal B cells, including RP11-24J23.2 (50 fold), RP11-12A2.3 (36 fold) and DLEU7-AS1 (19 fold). Quantitative RT-PCR (QRT-PCR) confirmed higher expression of RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 in MCL patient samples as compared to normal B cells. To investigate the biological significance of lncRNAs in MCL cells, we overexpressed RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 lncRNAs and analyzed effects on cell proliferation and apoptosis. To achieve overexpression lncRNAs, RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 were cloned individually in expression pcDNA3.1 generating constructs: pcDNA3RP11-24J23.2, pcDNA3RP11-12A2.3 and pcDNA3DLEU7-AS1and then transfected into MCL cell lines along with pcDNA3.1. QRT-PCR revealed effective overexpression (~100 fold increase over baseline) for each transfected lncRNAs construct in Granta and Mino cells. Analysis of proliferation and survival showed that overexpressing RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1 promotes cell proliferation and survival in these cells as compared to the vector controls. Most of the lncRNAs found so far have been linked to the transcriptional regulation of the target genes through their association with chromatin remodeling factors such as Polycomb Repressive Complex 2 (PRC2). To identify the functional relevance of RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 lncRNAs, we examined the binding of the lymphoma specific lncRNAs with PRC2 complex, by performing RNA immunoprecipitation (RNA-IP) using specific antibodies to EZH2, EED and SUZ12. The RNA-IP results demonstrate high affinity binding of all three lncRNAs with SUZ12 and EED but a weak binding with EZH2. Furthermore, RNA-IP using antibody to histone 3-lysine 27 trimethylation (H3K27me3), a suppressive histone mark associated with PRC2 complex, also showed efficient binding with RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1. These results suggest that RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 lncRNAs can directly associated with PRC2 complex at chromatin. To understand the mechanism of increased cell growth after overexpression of lncRNAs, RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1, we analyzed expression level of important genes signature of MCL pathogenesis that include cyclin D1, cyclin D3, c-Myc, P14, and SOX11, a member of the group C SOX (SRY-related HMG-box) transcription factor family. Our results demonstrate that overexpression of lncRNAs RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1 enhanced the levels of cyclin D1 (>2 fold) mRNA without any impact on cyclin D3 or c-Myc transcript levels. In contrast overexpression of RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1 lncRNAs decreased SOX11 (0.08, 0.1 and 0.06 respectively) and P14 (0.06, 0.7 and 0.40 respectively) mRNA expression in Mino cells. To gain understanding of the mechanism involved in the suppression of SOX11 by the lncRNAs, we performed Chromatin immunoprecipitation assays with EZH2, EED and SUZ12 antibodies on Mino cells transfected with pcDNA3RP11-24J23.2, pcDNA3RP11-12A2.3 and pcDNA3DLEU7-AS1 or vector control. The data showed that overexpression of RP11-12A2.3 and DLEU7-AS1 significantly increased the binding of EED and to a lesser extent of EZH2 to SOX11 promoter while the binding of SUZ12 to SOX11 promoter was not changed as compared to vector alone. In conclusion, our results imply that lncRNAs are overexpressed in the MCL. Moreover, lymphoma associated lncRNAs (RP11-24J23.2, RP11-12A2.3 and DLEU7-AS1) regulate SOX11 expression via PRC2 complex contributing towards growth of MCL cells. Specific nature of lncRNAs found in lymphoma samples suggests that lncRNAs can be used as potential biomarkers for mantle cell lymphoma. Disclosures No relevant conflicts of interest to declare.
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Zaletel, Ivan, Marija Schwirtlich, Milka Perović, Mirna Jovanović, Milena Stevanović, Selma Kanazir, and Nela Puškaš. "Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer’s Disease Are Associated with Altered Expression of SOXB Transcription Factors." Journal of Alzheimer's Disease 65, no. 3 (September 11, 2018): 963–76. http://dx.doi.org/10.3233/jad-180277.
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Chen, Fang, Chong-Chao Zhong, Chang-Chun Song, Shu-Wei Chen, Yang He, and Xiao-Ying Tan. "Molecular Characterization and Functional Analysis of Two Steroidogenic Genes TSPO and SMAD4 in Yellow Catfish." International Journal of Molecular Sciences 22, no. 9 (April 26, 2021): 4505. http://dx.doi.org/10.3390/ijms22094505.
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The steroid hormones are required for gonadal development in fish. The present study was undertaken to characterize the cDNA and promoter sequences of TSPO and SMAD4 genes in yellow catfish Pelteobagrus fulvidraco, explored the mRNA tissue expression and deciphered their promoter regions. Yellow catfish TSPO and SMAD4 shared the similar domains to the corresponding genes from other vertebrates. The TSPO and SMAD4 mRNAs were widely expressed in the detected tissues, but at different levels. Several transcription factors were predicted, such as Sp, GATA, AP1, SOX1, SRY, STAT, HNF4α, PPARγ, Pu.1 and FOXL2. PPARγ overexpression increased but STAT3 overexpression reduced TSPO promoter activity, and FOXL2 overexpression inhibited the promoter activity of TSPO and SMAD4. The site mutation and EMSA analysis indicated that TSPO promoter possessed STAT3 and FOXL2 sites. Overall, our provided the novel understanding into the transcriptionally regulatory mechanisms of TSPO and SMAD4 in fish.
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Seok, Jaekwon, Minchan Gil, Ahmed Abdal Dayem, Subbroto Kumar Saha, and Ssang-Goo Cho. "Multi-Omics Analysis of SOX4, SOX11, and SOX12 Expression and the Associated Pathways in Human Cancers." Journal of Personalized Medicine 11, no. 8 (August 23, 2021): 823. http://dx.doi.org/10.3390/jpm11080823.
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The Sry-related HMG BOX (SOX) gene family encodes transcription factors containing highly conserved high-mobility group domains that bind to the minor groove in DNA. Although some SOX genes are known to be associated with tumorigenesis and cancer progression, their expression and prognostic value have not been systematically studied. We performed multi-omic analysis to investigate the expression of SOX genes in human cancers. Expression and phylogenetic tree analyses of the SOX gene family revealed that the expression of three closely related SOX members, SOX4, SOX11, and SOX12, was increased in multiple cancers. Expression, mutation, and alteration of the three SOX members were evaluated using the Oncomine and cBioPortal databases, and the correlation between these genes and clinical outcomes in various cancers was examined using the Kaplan–Meier, PrognoScan, and R2 database analyses. The genes commonly correlated with the three SOX members were categorized in key pathways related to the cell cycle, mitosis, immune system, and cancer progression in liver cancer and sarcoma. Additionally, functional protein partners with three SOX proteins and their probable signaling pathways were explored using the STRING database. This study suggests the prognostic value of the expression of three SOX genes and their associated pathways in various human cancers.
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Gallegos-Cardenas, A., K. Wang, E. T. Jordan, R. West, F. D. West, J. Y. Yang, and S. L. Stice. "191 ROBUST GENERATION OF NEURAL STEM CELLS FROM PIG INDUCED PLURIPOTENT STEM CELLS FOR TRANSLATIONAL NEURAL REGENERATIVE MEDICINE." Reproduction, Fertility and Development 26, no. 1 (2014): 210. http://dx.doi.org/10.1071/rdv26n1ab191.
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The generation of pig induced pluripotent stem cells (iPSC) opened the possibility to evaluate autologous neural cell therapy as a viable option for human patients. However, it is necessary to demonstrate whether pig iPSC are capable of in vitro neural differentiation similar to human iPSC in order to perform in vitro and in vivo comparative studies. Multiple laboratories have generated pig iPSC that have been characterised using pluripotent markers such as SSEA4 and POU5F1. However, correlations of pluripotent marker expression profiles among iPSC lines and their neural differentiation potential has not been fully explored. Because neural rosettes (NR) are composed of neural stem cells, our goal was to demonstrate that NR from pig iPSC can be generated, isolated, and expanded in vitro from multiple porcine iPSC lines similar to human iPSC and that the level of pluripotency in the starting porcine iPSC population (POUF51 and SSEA4 expression) could influence NRs development. Three lines of pig iPSC L1, L2, and L3 were cultured on matrigel-coated plates in mTeSR1 medium (Stemcell Technologies Inc., Vancouver, BC, Canada) and passaged every 3 to 4 days. For neural induction (NI), pig iPSC were disaggregated using dispase and plated. After 24 h, cells were maintained in N2 media [77% DMEM/F12, 10 ng mL–1 bovine fibroblast growth factor (bFGF), and 1X N2] for 15 days. To evaluate the differentiation potential to neuron and glial cells, NR were isolated, expanded in vitro and cultured for three weeks in AB2 medium (AB2, 1X ANS, and 2 mM L-Glutamine). Immunostaining assays were performed to determine pluripotent (POU5F1 and SSEA4), tight junction (ZO1), neural epithelial (Pax6 and Sox1), neuron (Tuj1), astrocyte (GFAP), and oligodendrocyte (O4) marker expression. Line L2 (POU5F1high and SSEA4low) showed a high potential to form NR (6.3.5%, P < 0.05) in comparison to the other 2 lines L1 (POU5F1low and SSEA4low) and L3 (POU5F1low and SSEA4high) upon NI. The NR immunocytochemistry results from Line L2 showed the presence of Pax6+ and Sox1– NRs cells at day 9 post-neural induction and that ZO1 started to localise at the apical border of NRs. At day 13, NRs cells were Pax6+ and Sox1+, and ZO1 was localised to the lumen of NR. After isolation and culture in vitro, NR cells expressed transcription factors PLAGL1, DACH1, and OTX2 through 2 passages, but were not detected in later passages. However, rosette cytoarchitecture was present up until passage 7 and were still Pax6+/Sox1+. NRs at passage 2 were cryopreserved and upon thaw showed normal NR morphology and were Pax6+/Sox1+. To characterise the plasticity of NRs, cells were differentiated. Tuj1 expression was predominant after differentiation indicating a bias towards a neuron phenotype. These results demonstrate that L2 pig iPSC (POUF51high and SSEA4low) have a high potential to form NR and neural differentiation parallels human iPSC neurulation events. Porcine iPSC should be considered as a large animal model for determining the safety and efficacy of human iPSC neural cell therapies.
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Kishi, M., K. Mizuseki, N. Sasai, H. Yamazaki, K. Shiota, S. Nakanishi, and Y. Sasai. "Requirement of Sox2-mediated signaling for differentiation of early Xenopus neuroectoderm." Development 127, no. 4 (February 15, 2000): 791–800. http://dx.doi.org/10.1242/dev.127.4.791.
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From early stages of development, Sox2-class transcription factors (Sox1, Sox2 and Sox3) are expressed in neural tissues and sensory epithelia. In this report, we show that Sox2 function is required for neural differentiation of early Xenopus ectoderm. Microinjection of dominant-negative forms of Sox2 (dnSox2) mRNA inhibits neural differentiation of animal caps caused by attenuation of BMP signals. Expression of dnSox2 in developing embryos suppresses expression of N-CAM and regional neural markers. We have analyzed temporal requirement of Sox2-mediated signaling by using an inducible dnSox2 construct fused to the ligand-binding domain of the glucocorticoid receptor. Attenuation of Sox2 function both from the late blastula stage and from the late gastrula stage onwards causes an inhibition of neural differentiation in animal caps and in whole embryos. Additionally, dnSox2-injected cells that fail to differentiate into neural tissues are not able to adopt epidermal cell fate. These data suggest that Sox2-class genes are essential for early neuroectoderm cells to consolidate their neural identity during secondary steps of neural differentiation.
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Kallas-Kivi, Ade, Annika Trei, and Toivo Maimets. "Lovastatin Decreases the Expression of CD133 and Influences the Differentiation Potential of Human Embryonic Stem Cells." Stem Cells International 2016 (2016): 1–16. http://dx.doi.org/10.1155/2016/1580701.
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The lipophilic statin lovastatin decreases cholesterol synthesis and is a safe and effective treatment for the prevention of cardiovascular diseases. Growing evidence points at antitumor potential of lovastatin. Therefore, understanding the molecular mechanism of lovastatin function in different cell types is critical to effective therapy design. In this study, we investigated the effects of lovastatin on the differentiation potential of human embryonic stem (hES) cells (H9 cell line). Multiparameter flow cytometric assay was used to detect changes in the expression of transcription factors characteristic of hES cells. We found that lovastatin treatment delayed NANOG downregulation during ectodermal and endodermal differentiation. Likewise, expression of ectodermal (SOX1 and OTX2) and endodermal (GATA4 and FOXA2) markers was higher in treated cells. Exposure of hES cells to lovastatin led to a minor decrease in the expression of SSEA-3 and a significant reduction in CD133 expression. Treated cells also formed fewer embryoid bodies than control cells. By analyzing hES with and without CD133, we discovered that CD133 expression is required for proper formation of embryoid bodies. In conclusion, lovastatin reduced the heterogeneity of hES cells and impaired their differentiation potential.
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Baudouin-Gonzalez, Luis, Anna Schoenauer, Amber Harper, Grace Blakeley, Michael Seiter, Saad Arif, Lauren Sumner-Rooney, Steven Russell, Prashant P. Sharma, and Alistair P. McGregor. "The Evolution of Sox Gene Repertoires and Regulation of Segmentation in Arachnids." Molecular Biology and Evolution 38, no. 8 (March 23, 2021): 3153–69. http://dx.doi.org/10.1093/molbev/msab088.
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Abstract The Sox family of transcription factors regulates many processes during metazoan development, including stem cell maintenance and nervous system specification. Characterizing the repertoires and roles of these genes can therefore provide important insights into animal evolution and development. We further characterized the Sox repertoires of several arachnid species with and without an ancestral whole-genome duplication and compared their expression between the spider Parasteatoda tepidariorum and the harvestman Phalangium opilio. We found that most Sox families have been retained as ohnologs after whole-genome duplication and evidence for potential subfunctionalization and/or neofunctionalization events. Our results also suggest that Sox21b-1 likely regulated segmentation ancestrally in arachnids, playing a similar role to the closely related SoxB gene, Dichaete, in insects. We previously showed that Sox21b-1 is required for the simultaneous formation of prosomal segments and sequential addition of opisthosomal segments in P. tepidariorum. We studied the expression and function of Sox21b-1 further in this spider and found that although this gene regulates the generation of both prosomal and opisthosomal segments, it plays different roles in the formation of these tagmata reflecting their contrasting modes of segmentation and deployment of gene regulatory networks with different architectures.
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Equbal, Zaffar, Prakash N. Baligar, Madhulika Srivastava, and Asok Mukhopadhyay. "A Two-Stage Process for Differentiation of Wharton’s Jelly-Derived Mesenchymal Stem Cells into Neuronal-like Cells." Stem Cells International 2021 (May 28, 2021): 1–17. http://dx.doi.org/10.1155/2021/6631651.
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With no permanent cure for neurodegenerative diseases, the symptoms reappear shortly after the withdrawal of medicines. A better treatment outcome can be expected if the damaged neurons are partly replaced by functional neurons and/or they are repaired using trophic factors. In this regard, safe cell therapy has been considered as a potential alternative to conventional treatment. Here, we have described a two-stage culture process to differentiate Wharton Jelly mesenchymal stem cells (WJ-MSCs) into neuronal-like cells in the presence of various cues involved in neurogenesis. The fate of cells at the end of each stage was analyzed at the morphometric, transcriptional, and translational levels. In the first stage of priming, constitutively, wingless-activated WJ-MSCs crossed the lineage boundary in favor of neuroectodermal lineage, identified by the loss of mesenchymal genes with concomitant expression of neuron-specific markers, like SOX1, PAX6, NTRK1, and NEUROD2. Neuronal-like cells formed in the second stage expressed many mature neuronal proteins like Map2, neurofilament, and Tuj1 and possessed axon hillock-like structures. In conclusion, the differentiation of a large number of neuronal-like cells from nontumorigenic and trophic factors secreting WJ-MSCs promises the development of a therapeutic strategy to treat neurodegenerative diseases.
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Madhu, Vedavathi, Abhijit S. Dighe, Quanjun Cui, and D. Nicole Deal. "Dual Inhibition of Activin/Nodal/TGF-βand BMP Signaling Pathways by SB431542 and Dorsomorphin Induces Neuronal Differentiation of Human Adipose Derived Stem Cells." Stem Cells International 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/1035374.
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Damage to the nervous system can cause devastating diseases or musculoskeletal dysfunctions and transplantation of progenitor stem cells can be an excellent treatment option in this regard. Preclinical studies demonstrate that untreated stem cells, unlike stem cells activated to differentiate into neuronal lineage, do not survive in the neuronal tissues. Conventional methods of inducing neuronal differentiation of stem cells are complex and expensive. We therefore sought to determine if a simple, one-step, and cost effective method, previously reported to induce neuronal differentiation of embryonic stem cells and induced-pluripotent stem cells, can be applied to adult stem cells. Indeed, dual inhibition of activin/nodal/TGF-βand BMP pathways using SB431542 and dorsomorphin, respectively, induced neuronal differentiation of human adipose derived stem cells (hADSCs) as evidenced by formation of neurite extensions, protein expression of neuron-specific gamma enolase, and mRNA expression of neuron-specific transcription factors Sox1 and Pax6 and matured neuronal marker NF200. This process correlated with enhanced phosphorylation of p38, Erk1/2, PI3K, and Akt1/3. Additionally,in vitrosubcutaneous implants of SB431542 and dorsomorphin treated hADSCs displayed significantly higher expression of active-axonal-growth-specific marker GAP43. Our data offers novel insights into cell-based therapies for the nervous system repair.
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Liu, Bing-Chun, Fang-Yuan Liu, Xin-Yue Gao, Yang-Lin Chen, Qiao-Qiao Meng, Yong-Li Song, Xi-He Li, and Si-Qin Bao. "Global Transcriptional Analyses of the Wnt-Induced Development of Neural Stem Cells from Human Pluripotent Stem Cells." International Journal of Molecular Sciences 22, no. 14 (July 12, 2021): 7473. http://dx.doi.org/10.3390/ijms22147473.
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The differentiation of human pluripotent stem cells (hPSCs) to neural stem cells (NSCs) is the key initial event in neurogenesis and is thought to be dependent on the family of Wnt growth factors, their receptors and signaling proteins. The delineation of the transcriptional pathways that mediate Wnt-induced hPSCs to NSCs differentiation is vital for understanding the global genomic mechanisms of the development of NSCs and, potentially, the creation of new protocols in regenerative medicine. To understand the genomic mechanism of Wnt signaling during NSCs development, we treated hPSCs with Wnt activator (CHIR-99021) and leukemia inhibitory factor (LIF) in a chemically defined medium (N2B27) to induce NSCs, referred to as CLNSCs. The CLNSCs were subcultured for more than 40 passages in vitro; were positive for AP staining; expressed neural progenitor markers such as NESTIN, PAX6, SOX2, and SOX1; and were able to differentiate into three neural lineage cells: neurons, astrocytes, and oligodendrocytes in vitro. Our transcriptome analyses revealed that the Wnt and Hedgehog signaling pathways regulate hPSCs cell fate decisions for neural lineages and maintain the self-renewal of CLNSCs. One interesting network could be the deregulation of the Wnt/β-catenin signaling pathway in CLNSCs via the downregulation of c-MYC, which may promote exit from pluripotency and neural differentiation. The Wnt-induced spinal markers HOXA1-4, HOXA7, HOXB1-4, and HOXC4 were increased, however, the brain markers FOXG1 and OTX2, were absent in the CLNSCs, indicating that CLNSCs have partial spinal cord properties. Finally, a CLNSC simple culture condition, when applied to hPSCs, supports the generation of NSCs, and provides a new and efficient cell model with which to untangle the mechanisms during neurogenesis.
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Szczepanek, Joanna, Joanna Laskowska, Agata Labedzka, Jan Styczynski, and Andrzej Tretyn. "Genetic Mechanisms Of Cytarabine, Etoposide and Daunorubicin Resistance In Pediatric Acute Leukemias." Blood 122, no. 21 (November 15, 2013): 4938. http://dx.doi.org/10.1182/blood.v122.21.4938.4938.
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Abstract Introduction Drug resistance is a major problem in chemotherapy of leukemia. Several mechanisms of this phenomenon have been identified, but the underlying genomic changes are still poorly understood. Lack of drug sensitivity arises from a complex range of molecular events, which ultimately result in the blasts escaping death. Analysis of the gene expression profiles of cancer cells in correlation with in vitro cytotoxicity assay may define mechanisms of sensitivity and resistance to specific drugs. OBJECTIVE: To define and compare whole-genome responses to cytarabine (Ara-C), etoposide (VP16) and daunorubicin (DNR) in pediatric patients diagnosed with acute leukemias, and to explain in vitro chemoresistance phenotype of leukemic blasts. Methods In order to determine the ex vivo drug resistance profile, MTT cytotoxicity assay was performed on mononuclear cells obtained from 51 patients with ALL and 16 patients with AML. Gene expression profiles were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were performed during the correlation analysis for identified probe sets. Verification of the relative expression level of genes (EGR1, GATA2, RUFY3, LDHA, DUSP2, BIN2, ICAM3, TTC28) was carried out by RT-qPCR in the study group and in an independent group of 53 patients. Results Genetic expression profiles were identified, including those appropriate for ALL and AML: 181 and 106 genes for Ara-C, 274 and 314 for VP16, 146 and 495 for the DNR. For each of the drugs, a characteristic group of genes or processes that are responsible for the lack of sensitivity, were identified: (1) for Ara-C: overexpression of genes responsible for removing the drug from the cells, as well as changes in the nucleic acid metabolic process, especially transcription from RNA polymerase II promoter (eg. ZBTB16, FOSB, NFATC1, ZNF518B, PHF20L1 and RUFY); (2) for VP16: changes in expression level of genes involved in the regulation of mRNA transcription and DNA metabolism genes, including those controlling replication as well as those belonging to the double helix damage repair enzymes and genes participating in post-transcriptional mRNA splicing (eg. TOP2B, CSNK1E, BRIP1, ATR, MSH3 and MSH6); (3) for DNR: differentiated expression of factors involved in the replication and transcription processes, increased expression of kinases and intensification of the DNA repair processes (eg. ATF2, GATA2, TOX, RUNX3, MNDA, ST18, TFDP1, NFE2, SOX11 and PAX5). For each profile several common genes, such as: AGAP1, PRKCH, RAB31, BCL2A1, GCA, HLA-DRA, HLA-DPA1, IL8, RGS10, CEBPD, CLEC2, ANXA1, PLEK, S100A8, SLC, CXCL2, SOX, BTG, DEFA4 and TPD52, were identified. Pathway and functional gene ontology analysis showed that several features, independent of the initial type of leukemia cells and pattern of resistance include: overexpression of chemokines and hydrolases, increase in the expression of genes responsible for the maintenance of chromatin architecture, overexpression of anti-apoptotic genes, decrease in expression level of genes that promote apoptosis, decrease in gene expression of Wnt signaling pathway, down regulation of the expression of transcription factors, changes in the expression level of genes associated with the activation of B and T lymphocytes, differences in expression of genes responsible for the cell surface receptor linked signal transduction and intracellular signaling cascade. Conclusions This analysis showed that the mechanism of response to drugs is significantly genetically determined. Predictive sets of marker genes and functional groups for simultaneous assessment of the sensitivity to these 3 drugs, were identified. Many of these changes converge and ultimately lead to avoidance of apoptosis and further over-proliferation of cancer cells. This could also suggest that targeting these pathways as potential pharmacogenetics and therapeutic candidates may be useful for improving treatment outcomes in pediatric acute leukemias. This could also suggest that targeting these pathways as potential pharmacogenetics and therapeutic candidates may be useful for improving treatment outcomes. Acknowledgments: This study was supported by Grant from the National Science Centre No. DEC-2011/03/D/NZ5/05749. Disclosures: No relevant conflicts of interest to declare.
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Kucia, Magda, Rui Liu, Kasia Mierzejewska, Wan Wu, Janina Ratajczak, Dong-Myung Shin, and Mariusz Z. Ratajczak. "Single Cell Level Genome-Wide Gene Expression Analysis of Bone Marrow-Derived Oct-4+ very Small Embryonic-Like Stem Cells (VSELs) Revealed That a Polycomb Group Protein Ezh2 Regulates VSELs Pluripotency by Maintaining Bivalent Domains At Promoters of Important Homeodomain-Containing Developmental Transcription Factors." Blood 118, no. 21 (November 18, 2011): 2345. http://dx.doi.org/10.1182/blood.v118.21.2345.2345.
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Abstract Abstract 2345 Recently, we identified a population of very small embryonic-like (VSEL) stem cells (SCs) in adult bone marrow (BM) (Leukemia 2006:20;857). These Oct4+CXCR4+SSEA-1+Sca-1+CD45−Lin− VSELs are capable of differentiation in vitro into cells from all three germ lineages and in in vivo animal models they can be specified into mesenchymal stem cells (MSCs) (Stem Cells Dev 2010:19;1557), cardiomyocytes (Stem Cell 2008:26;1646), and long-term engrafting hematopoietic stem cells (HSCs) (Exp Hematol 2011:39;225). Be employing gene-expression and epigenetic profiling studies we reported that VSELs in BM have germ-line stem cell like epigenetic features including i) open/active chromatin structure in Oct4 promoter, ii) parent-of-origin specific reprogramming of genomic imprinting (Leukemia 2009, 23, 2042–2051), and iii) that they share several markers with epiblast-derived primordial germ cells (PGCs), in particular with migratory PGCs (Leukemia 2010, 24, 1450–1461). However, it was not clear how VSELs maintain pluripotent state. To address this issue we recently employed single cell-based genome-wide gene expression analysis and found that, Oct4+ VSELs i) express a similar, yet nonidentical, transcriptome as embryonic stem-cells (ESCs), ii) up-regulate cell-cycle checkpoint genes, and iii) down-regulate genes involved in protein turnover and mitogenic pathways. Interestingly, our single cell library studies also revelaed that Ezh2, a polycomb group protein, is highly expressed in VSELs. This protein is well known to be involved in maintaining a bivalent domains (BDs) at promoters of important homeodomain-containing developmental transcription factors. Of note a presence of BDs is characteristic for pluripotent stem cells (e.g., ESCs) and as result of Ezh2 overexpression, VSELs, like ESCs, exhibit BDs - bivalently modified nucleosomes (trimethylated H3K27 and H3K4) at promoters of important homeodomain-containing developmental transcription factors (Sox21 Nkx2.2 Dlx1 Zfpm2 Irx2 Lbx1h Hlxb9 Pax5 HoxA3). Of note, spontaneous (as seen during differentiation) or RNA interference-enforced down-regulation of Ezh2 removes BDs what, results in lose of their plurioptentiality and de-repression of several BD-regulated genes that control their tissue commitment. In conclusion, Our results show for first time that in addition to the expression of pluripotency core transcription factor Oct-4, VSELs, like other pluripotent stem-cells, maintain their pluripotent state through an Ezh2-dependent BD-mediated epigenetic mechanism. Based on this our genome-wide gene expression study not only advances our understanding of biological processes that govern VSELs pluripotency, differentiation, and quiescence but will also help to develop better protocols for ex vivo expansion of these promising cells for potential application in regenerative medicine. Disclosures: Ratajczak: Neostem Inc: Consultancy, Research Funding.