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Eliseeva, I. A., E. R. Kim, S. G. Guryanov, L. P. Ovchinnikov, and D. N. Lyabin. "Y-box-binding protein 1 (YB-1) and its functions." Biochemistry (Moscow) 76, no. 13 (December 2011): 1402–33. http://dx.doi.org/10.1134/s0006297911130049.
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Matsumoto, Ken, Kimio J. Tanaka, and Masafumi Tsujimoto. "An Acidic Protein, YBAP1, Mediates the Release of YB-1 from mRNA and Relieves the Translational Repression Activity of YB-1." Molecular and Cellular Biology 25, no. 5 (March 1, 2005): 1779–92. http://dx.doi.org/10.1128/mcb.25.5.1779-1792.2005.
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ABSTRACT Eukaryotic Y-box proteins are nucleic acid-binding proteins implicated in a wide range of gene regulatory mechanisms. They contain the cold shock domain, which is a nucleic acid-binding structure also found in bacterial cold shock proteins. The Y-box protein YB-1 is known to be a core component of messenger ribonucleoprotein particles (mRNPs) in the cytoplasm. Here we disrupted the YB-1 gene in chicken DT40 cells. Through the immunoprecipitation of an epitope-tagged YB-1 protein, which complemented the slow-growth phenotype of YB-1-depleted cells, we isolated YB-1-associated complexes that likely represented general mRNPs in somatic cells. RNase treatment prior to immunoprecipitation led to the identification of a Y-box protein-associated acidic protein (YBAP1). The specific association of YB-1 with YBAP1 resulted in the release of YB-1 from reconstituted YB-1-mRNA complexes, thereby reducing the translational repression caused by YB-1 in the in vitro system. Our data suggest that YBAP1 induces the remodeling of YB-1-mRNA complexes.
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Naumenko, Konstantin N., Mariya V. Sukhanova, Loic Hamon, Tatyana A. Kurgina, Elizaveta E. Alemasova, Mikhail M. Kutuzov, David Pastré, and Olga I. Lavrik. "Regulation of Poly(ADP-Ribose) Polymerase 1 Activity by Y-Box-Binding Protein 1." Biomolecules 10, no. 9 (September 16, 2020): 1325. http://dx.doi.org/10.3390/biom10091325.
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Y-box-binding protein 1 (YB-1) is a multifunctional positively charged protein that interacts with DNA or RNA and poly(ADP-ribose) (PAR). YB-1 is poly(ADP-ribosyl)ated and stimulates poly(ADP-ribose) polymerase 1 (PARP1) activity. Here, we studied the mechanism of YB-1-dependent PAR synthesis by PARP1 in vitro using biochemical and atomic force microscopy assays. PAR synthesis activity of PARP1 is known to be facilitated by co-factors such as Mg2+. However, in contrast to an Mg2+-dependent reaction, the activation of PARP1 by YB-1 is accompanied by overall up-regulation of protein PARylation and shortening of the PAR polymer. Therefore, YB-1 and cation co-factors stimulated PAR synthesis in divergent ways. PARP1 autoPARylation in the presence of YB-1 as well as trans-PARylation of YB-1 are greatly affected by the type of damaged DNA, suggesting that PARP1 activation depends on the formation of a PARP1–YB-1–DNA ternary complex. An unstructured C-terminal part of YB-1 involved in an interaction with PAR behaves similarly to full-length YB-1, indicating that both DNA and PAR binding are involved in the stimulation of PARP1 activity by YB-1. Thus, YB-1 is likely linked to the regulation of PARylation events in cells via an interaction with PAR and damaged DNA.
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Bader, Andreas G., and Peter K. Vogt. "Inhibition of Protein Synthesis by Y Box-Binding Protein 1 Blocks Oncogenic Cell Transformation." Molecular and Cellular Biology 25, no. 6 (March 15, 2005): 2095–106. http://dx.doi.org/10.1128/mcb.25.6.2095-2106.2005.
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ABSTRACT The multifunctional Y box-binding protein 1 (YB-1) is transcriptionally repressed by the oncogenic phosphoinositide 3-kinase (PI3K) pathway (with P3K as an oncogenic homolog of the catalytic subunit) and, when reexpressed with the retroviral vector RCAS, interferes with P3K- and Akt-induced transformation of chicken embryo fibroblasts. Retrovirally expressed YB-1 binds to the cap of mRNAs and inhibits cap-dependent and cap-independent translation. To determine the requirements for the inhibitory role of YB-1 in P3K-induced transformation, we conducted a mutational analysis, measuring YB-1-induced interference with transformation, subcellular localization, cap binding, mRNA binding, homodimerization, and inhibition of translation. The results show that (i) interference with transformation requires RNA binding and a C-terminal domain that is distinct from the cytoplasmic retention domain, (ii) interference with transformation is tightly correlated with inhibition of translation, and (iii) masking of mRNAs by YB-1 is not sufficient to block transformation or to inhibit translation. We identified a noncanonical nuclear localization signal (NLS) in the C-terminal half of YB-1. A mutant lacking the NLS retains its ability to interfere with transformation, indicating that a nuclear function is not required. These results suggest that YB-1 interferes with P3K-induced transformation by a specific inhibition of translation through its RNA-binding domain and a region in the C-terminal domain. Potential functions of the C-terminal region are discussed.
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Lyabin, Dmitry N., Alexander N. Doronin, Irina A. Eliseeva, Gelena P. Guens, Ivan V. Kulakovskiy, and Lev P. Ovchinnikov. "Alternative Forms of Y-Box Binding Protein 1 and YB-1 mRNA." PLoS ONE 9, no. 8 (August 12, 2014): e104513. http://dx.doi.org/10.1371/journal.pone.0104513.
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Ke, Ben, Chuqiao Fan, Weiping Tu, and Xiangdong Fang. "The Role of Y-Box Binding Protein 1 in Kidney Injury: Friend or Foe?" Cellular Physiology and Biochemistry 46, no. 1 (2018): 314–21. http://dx.doi.org/10.1159/000488432.
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Y-box-binding protein 1 (YB-1) is a multifunctional protein involved in various cellular processes via the transcriptional and translational regulation of target gene expression. YB-1 promotes acute or chronic kidney injury through multiple molecular pathways; however, accumulating evidence suggests that significantly increased YB-1 levels are of great importance in renoprotection. In addition, YB-1 may contribute to obesity-related kidney disease by promoting adipogenesis. Thus, the role of YB-1 in kidney injury is complicated, and no comprehensive review is currently available. In this review, we summarise recent progress in our understanding of the function of YB-1 in kidney injury and provide an overview of the dual role of YB-1 in kidney disease. Moreover, we propose that YB-1 is a potential therapeutic target to restrict kidney disease.
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Meyer, Nicole, Anne Schumacher, Urs Coenen, Katja Woidacki, Hannah Schmidt, Jonathan A. Lindquist, Peter R. Mertens, and Ana C. Zenclussen. "Y-Box Binding Protein 1 Expression in Trophoblast Cells Promotes Fetal and Placental Development." Cells 9, no. 9 (August 22, 2020): 1942. http://dx.doi.org/10.3390/cells9091942.
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Y-box binding protein 1 (YB-1) is pivotal for the regulation of cancerogenesis and inflammation. However, its involvement in pregnancy processes such as fetal and placental development remains to be elucidated. We studied Ybx1 (YB-1)+/− heterozygous intercrossings and compared them to YB-1+/+ wild-type (WT) combinations. Additionally, we generated trophoblast-specific YB-1-deficient mice by pairing FVB Cyp19-Cre females to YB-1fl/fl males. YB-1fl/fl-paired FVB WT females served as controls. Serial in vivo ultrasound measurements were performed to assess fetal and placental parameters. After sacrificing the females, implantation and abortion rates were recorded, spiral artery (SA) remodeling was analyzed and fetal and placental weights were determined. Compared to YB-1+/+ counterparts, YB-1+/− females showed reduced implantation areas at gestation day (GD)10, insufficiently remodeled SAs at GD12, increased placental diameter/thickness ratios at GD14 and reduced placental and fetal weights at GD14. Compared to WT, Cyp19-Cre females with YB-1-deficient placentas showed reduced implantation areas at GD8, 10 and 12; decreased placental areas and diameters at GD10 and 12; diminished placental thicknesses at GD12; as well as reduced placental weights at GD12 and 14. In conclusion, our data suggest haploinsufficiency of YB-1 resulting in disturbed fetal and placental development. Moreover, we provide the first evidence for the relevance of trophoblast-specific YB-1 for placentation.
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Kohno, Kimitoshi, Hiroto Izumi, Takeshi Uchiumi, Megumi Ashizuka, and Michihiko Kuwano. "The pleiotropic functions of the Y-box-binding protein, YB-1." BioEssays 25, no. 7 (June 13, 2003): 691–98. http://dx.doi.org/10.1002/bies.10300.
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Yang, Xiao-Juan, Hong Zhu, Shi-Rong Mu, Wen-Juan Wei, Xun Yuan, Meng Wang, Yanchao Liu, Jingyi Hui, and Ying Huang. "Crystal structure of a Y-box binding protein 1 (YB-1)–RNA complex reveals key features and residues interacting with RNA." Journal of Biological Chemistry 294, no. 28 (June 3, 2019): 10998–1010. http://dx.doi.org/10.1074/jbc.ra119.007545.
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The Y-box binding protein 1 (YB-1) is a member of the cold shock domain (CSD) protein family and is recognized as an oncogenic factor in several solid tumors. By binding to RNA, YB-1 participates in several steps of posttranscriptional regulation of gene expression, including mRNA splicing, stability, and translation; microRNA processing; and stress granule assembly. However, the mechanisms in YB-1–mediated regulation of RNAs are unclear. Previously, we used both systematic evolution of ligands by exponential enrichment (SELEX) and individual-nucleotide resolution UV cross-linking and immunoprecipitation coupled RNA-Seq (iCLIP-Seq) analyses, which defined the RNA-binding consensus sequence of YB-1 as CA(U/C)C. We also reported that through binding to its core motif CAUC in primary transcripts, YB-1 regulates the alternative splicing of a CD44 variable exon and the biogenesis of miR-29b-2 during both Drosha and Dicer steps. To elucidate the molecular basis of the YB-1–RNA interactions, we report high-resolution crystal structures of the YB-1 CSD in complex with different RNA oligos at 1.7 Å resolution. The structure revealed that CSD interacts with RNA mainly through π–π stacking interactions assembled by four highly conserved aromatic residues. Interestingly, YB-1 CSD forms a homodimer in solution, and we observed that two residues, Tyr-99 and Asp-105, at the dimer interface are important for YB-1 CSD dimerization. Substituting these two residues with Ala reduced CSD's RNA-binding activity and abrogated the splicing activation of YB-1 targets. The YB-1 CSD–RNA structures presented here at atomic resolution provide mechanistic insights into gene expression regulated by CSD-containing proteins.
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Shiota, Masaki, Ario Takeuchi, YooHyun Song, Akira Yokomizo, Eiji Kashiwagi, Takeshi Uchiumi, Kentaro Kuroiwa, et al. "Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression." Endocrine-Related Cancer 18, no. 4 (June 7, 2011): 505–17. http://dx.doi.org/10.1530/erc-11-0017.
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The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcription factor that is upregulated in CPRC. We aimed to elucidate the role of YB-1 in castration resistance of PCa and identify therapeutic potential of targeting YB-1. Using immunohistochemistry, we found that nuclear YB-1 expression significantly correlated with the Gleason score and AR expression in PCa tissues. In PCa cells, YB-1 regulated AR expression at the transcriptional level. Furthermore, YB-1 expression and nuclear localization were upregulated in CRPC cells. Overexpression of AR, as well as YB-1, conferred castration-resistant growth in LNCaP and 22Rv1 cells. Conversely, knocking down YB-1 resulted in suppressed cell growth and induced apoptosis, which was more efficient than knocking down AR in LNCaP cells. In other types of PCa cells, such as CRPC cells, knocking down YB-1 resulted in a significant reduction of cell growth. In conclusion, these findings suggested that YB-1 induces castration resistance in androgen-dependent PCa cells via AR expression. Thus, YB-1 may be a promising therapeutic target for PCa, as well as CRPC.
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Liao, Li-Zhu, Chih-Ta Chen, Nien-Chen Li, Liang-Chun Lin, Bo-Shih Huang, Ya-Hui Chang, and Lu-Ping Chow. "Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells." International Journal of Molecular Sciences 22, no. 1 (December 28, 2020): 224. http://dx.doi.org/10.3390/ijms22010224.
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Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7R cells. Phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) were activated by sorafenib, which, in turn, increased the phosphorylation level of YB-1. In functional analyses, knockdown of YB-1 led to decreased cell migration and invasion in vitro. At the molecular level, inhibition of YB-1 induced suppression of zinc-finger protein SNAI1 (Snail), twist-related protein 1 (Twist1), zinc-finger E-box-binding homeobox 1 (Zeb1), matrix metalloproteinase-2 (MMP-2) and vimentin levels, implying a role of YB-1 in the epithelial-mesenchymal transition (EMT) process in HuH-7R cells. Additionally, YB-1 contributes to morphological alterations resulting from F-actin rearrangement through Cdc42 activation. Mutation analyses revealed that phosphorylation at S102 affects the migratory and invasive potential of HuH-7R cells. Our collective findings suggest that sorafenib promotes YB-1 phosphorylation through effect from the EGFR/PI3K/AKT pathway, leading to significant enhancement of hepatocellular carcinoma (HCC) cell metastasis. Elucidation of the specific mechanisms of action of YB-1 may aid in the development of effective strategies to suppress metastasis and overcome resistance.
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Matsumoto, Shinya, Takeshi Uchiumi, Hiroyuki Tanamachi, Toshiro Saito, Mikako Yagi, Shinya Takazaki, Tomotake Kanki, and Dongchon Kang. "Ribonucleoprotein Y-box-binding protein-1 regulates mitochondrial oxidative phosphorylation (OXPHOS) protein expression after serum stimulation through binding to OXPHOS mRNA." Biochemical Journal 443, no. 2 (March 27, 2012): 573–84. http://dx.doi.org/10.1042/bj20111728.
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Mitochondria play key roles in essential cellular functions, such as energy production, metabolic pathways and aging. Growth factor-mediated expression of the mitochondrial OXPHOS (oxidative phosphorylation) complex proteins has been proposed to play a fundamental role in metabolic homoeostasis. Although protein translation is affected by general RNA-binding proteins, very little is known about the mechanism involved in mitochondrial OXPHOS protein translation. In the present study, serum stimulation induced nuclear-encoded OXPHOS protein expression, such as NDUFA9 [NADH dehydrogenase (ubiquinone) 1α subcomplex, 9, 39 kDa], NDUFB8 [NADH dehydrogenase (ubiquinone) 1β subcomplex, 8, 19 kDa], SDHB [succinate dehydrogenase complex, subunit B, iron sulfur (Ip)] and UQCRFS1 (ubiquinol-cytochrome c reductase, Rieske iron–sulfur polypeptide 1), and mitochondrial ATP production, in a translation-dependent manner. We also observed that the major ribonucleoprotein YB-1 (Y-box-binding protein-1) preferentially bound to these OXPHOS mRNAs and regulated the recruitment of mRNAs from inactive mRNPs (messenger ribonucleoprotein particles) to active polysomes. YB-1 depletion led to up-regulation of mitochondrial function through induction of OXPHOS protein translation from inactive mRNP release. In contrast, YB-1 overexpression suppressed the translation of these OXPHOS mRNAs through reduced polysome formation, suggesting that YB-1 regulated the translation of mitochondrial OXPHOS mRNAs through mRNA binding. Taken together, our findings suggest that YB-1 is a critical factor for translation that may control OXPHOS activity.
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Gao, Dongyang, Qian Niu, Yuwen Gong, Qi Guo, Su Zhang, Yuhan Wang, Shanhui Liu, et al. "Y-Box Binding Protein 1 Regulates Angiogenesis in Bladder Cancer via miR-29b-3p-VEGFA Pathway." Journal of Oncology 2021 (July 1, 2021): 1–9. http://dx.doi.org/10.1155/2021/9913015.
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Angiogenesis plays a vital role in the development of bladder cancer (BC). The Y-box-binding protein 1 (YB-1) is a well-known oncoprotein which is closely related to angiogenesis of tumors, but the relationship and mechanism of YB-1 and angiogenesis in BC remain unclear. Based on 56 clinical BC specimens, this study found that high expression of YB-1 samples demonstrated a higher expression of vascular endothelial growth factor A (VEGFA) than those of YB-1 low expression. Subsequently, the expression of YB-1 and miR-29b-3p was regulated in the BC cell lines where we noted that YB-1 promoted VEGFA expression by downregulating the expression of miR- 29b-3p. The ability of BC cells to induce angiogenesis decreased after YB-1 was knocked down. Moreover, the in vivo study further confirmed that YB-1 promotes angiogenesis in BC. Our findings enhance the understanding of how YB-1 promotes angiogenesis in BC and provide evidence for YB-1 as a therapeutic target of BC. Moreover, this may provide new inspiration for miRNAs replacement therapies.
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Safak, Mahmut, Gary L. Gallia, Sameer A. Ansari, and Kamel Khalili. "Physical and Functional Interaction between the Y-Box Binding Protein YB-1 and Human Polyomavirus JC Virus Large T Antigen." Journal of Virology 73, no. 12 (December 1, 1999): 10146–57. http://dx.doi.org/10.1128/jvi.73.12.10146-10157.1999.
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ABSTRACT Y-box binding protein YB-1 is a member of a family of DNA and RNA binding proteins which have been shown to affect gene expression at both the transcriptional and translational levels. We have previously shown that YB-1 modulates transcription from the promoters of the ubiquitous human polyomavirus JC virus (JCV). Here we investigate the physical and functional interplay between YB-1 and the viral regulatory protein large T antigen (T-antigen), using JCV as a model system. Results of mobility band shift assays demonstrated that the efficiency of binding of YB-1 to a 23-bp single-stranded viral target sequence was significantly increased when T-antigen was included in the binding reaction mixture. Affinity chromatography and coimmunoprecipitation assays demonstrated that YB-1 and T-antigen physically interact with each other. Additionally, results of transcription studies demonstrated that these two proteins interact functionally on the JCV early and late gene promoters. Whereas ectopic expression of YB-1 and T-antigen results in synergistic transactivation of the viral late promoter, YB-1 alleviates T-antigen-mediated transcriptional suppression of the viral early promoter activity. Furthermore, we have localized, through the use of a series of deletion mutants, the sequences of these proteins which are important for their interaction. The T-antigen-interacting region of YB-1 is located in the cold shock domain of YB-1 and its immediate flanking sequences, and the YB-1-interacting domain of T-antigen maps to the carboxy-terminal half of T-antigen. Results of transient transfection assays with various YB-1 mutants and T-antigen expression constructs confirm the specificity of the functional interaction between YB-1 and T-antigen. Taken together, these data demonstrate that the cellular factor YB-1 and the viral regulatory protein T-antigen interact both physically and functionally and that this interaction modulates transcription from the JCV promoters.
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CHENG, Sunfa, Maria Alexandra ALFONSO-JAUME, Peter R. MERTENS, and David H. LOVETT. "Tumour metastasis suppressor, nm23-β, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1)." Biochemical Journal 366, no. 3 (September 15, 2002): 807–16. http://dx.doi.org/10.1042/bj20020202.
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Gelatinase A transcriptional regulation is the consequence of combinatorial interactions with key promoter and enhancer elements identified within this gene. A potent 40bp enhancer response element, RE-1, located in the near 5′ flanking regions of the rat and human gelatinase A genes drives high-level expression in glomerular mesangial cells (MCs). Southwestern-blot analysis of MC nuclear extracts revealed specific interactions of RE-1 with at least four proteins, of which three have been identified as p53, activator protein 2 and the single-stranded DNA-binding factor Y-box protein-1 (YB-1). In the present study, we report the identification of a fourth 17kDa RE-1-binding protein as the rat homologue (nm23-β) of the human nm23-H1 metastasis suppressor gene. Recombinant nm23-β protein bound only the single-stranded forms of the RE-1 sequence. Mutagenesis revealed direct interaction of nm23-β with a repeat sequence, 5′-GGGTTT-3′, shown previously to specifically interact with YB-1 [Mertens, Harendza, Pollock and Lovett (1997) J. Biol. Chem. 272, 22905—22912], and recombinant nm23-β protein competed for single-stranded YB-1 binding. Transient transfection of MC with an nm23-β expression plasmid within the context of a RE-1/simian virus 40 promoter/luciferase reporter yielded a concentration-dependent repression (80—90%) of luciferase activity in MC and Rat1 fibroblasts. A similar pattern of nm23-β repression was demonstrated within the context of the RE-1/homologous gelatinase A promoter. Co-transfection of nm23-β blocked YB-1-mediated activation of transcription and expression of gelatinase A. Nm23-β may be an important physiological regulator of gelatinase A transcription that acts by competitive interference with the single-stranded transactivator YB-1. Gelatinase A is a key mediator of tumour metastasis, suggesting that competitive suppression of transcription by nm23-β (or the human nm23-H1) may be a component of the reduced metastatic capabilities of cells expressing high levels of this protein.
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Khandelwal, Payal, Mythili K. Padala, John Cox, and Ramareddy V. Guntaka. "The N-Terminal Domain of Y-Box Binding Protein-1 Induces Cell Cycle Arrest in G2/M Phase by Binding to Cyclin D1." International Journal of Cell Biology 2009 (2009): 1–11. http://dx.doi.org/10.1155/2009/243532.
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Y-box binding protein YB-1 is a multifunctional protein involved in cell proliferation, regulation of transcription and translation. Our previous study indicated that disruption of one allele of Chk-YB-1b gene in DT-40 cells resulted in major defects in the cell cycle. The abnormalities seen in heterozygous mutants could be attributed to a dominant negative effect exerted by the disrupted YB-1 allele product. To test this hypothesis the N-terminal sequence of the YB-1 was fused with the third helix of antennapedia and the green fluorescent protein. These purified fusion proteins were introduced into rat hepatoma cells and their effect on cell proliferation was studied. Results indicate that the N-terminal 77 amino acid domain of the YB-1 protein induced the cells to arrest in G2/M phase of the cell cycle and undergo apoptosis. Additional deletion analysis indicated that as few as 26 amino acids of the N-terminus of YB-1 can cause these phenotypic changes. We further demonstrated that this N-terminal 77 amino acid domain of YB-1 sequesters cyclin D1 in the cytoplasm of cells at G2/M phase of cell cycle. We conclude that the N-terminal domain of YB-1 plays a major role in cell cycle progression through G2/M phase of cell cycle.
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SAMUEL, Shaija, Jean-Claude TWIZERE, and Lori R. BERNSTEIN. "YB-1 represses AP1-dependent gene transactivation and interacts with an AP-1 DNA sequence." Biochemical Journal 388, no. 3 (June 7, 2005): 921–28. http://dx.doi.org/10.1042/bj20041497.
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Involvement of the AP-1 (activator protein-1) transcription factor has been demonstrated previously in the regulation of cell proliferation and cell-cycle progression, in the control of cell migration, invasion and metastasis, and in signal transduction, stress responsiveness, DNA replication and DNA repair. YB-1 (Y-box-binding protein-1) has also been implicated in many of these processes. However, the mechanism by which YB-1 mediates these processes is poorly understood. In the present study, we report that overexpression of a transfected gene encoding YB-1 in human HeLa cervical carcinoma cells significantly represses the transactivation of a minimal AP-1 reporter construct in response to the tumour promoter PMA. YB-1 also represses mRNA expression and PMA-induced promoter transactivation of the endogenous AP-1 target gene encoding matrix metalloproteinase-12 (metalloelastase). YB-1 transrepression of both the minimal and matrix metalloproteinase-12 promoter reporter constructs is dependent on the AP-1 sequence. To identify new nuclear proteins that bind specifically to the AP-1 DNA-binding site, we devised a DNA-affinity-chromatography-based assay termed NAPSTER (nucleotide-affinity preincubation specificity test of recognition) and discovered a 49 kDa protein from human cancer cells that binds in a sequence-specific manner to the AP-1 DNA sequence. By tandem MS fragmentation sequencing analyses we determined that p49 is a YB-1. Immunoblotting of the NAPSTER-purified p49 protein using anti-YB-1 antibodies confirmed YB-1 binding to the AP-1 DNA sequence, as did gel mobility-supershift assays using YB-1 antibodies. This is the first report of YB-1 transrepression and interaction at the AP-1 DNA-binding site.
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Gunasekaran, Vinoth Prasanna, Kumari Nishi, Vilwanathan Ravikumar, and Ganeshan Mathan. "Nuclear shuttling of Y Box binding protein-1, its clinical relevance in cancer and as a therapeutic target." Bangladesh Journal of Pharmacology 11, no. 2 (April 30, 2016): 501. http://dx.doi.org/10.3329/bjp.v11i2.26759.
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<p class="Abstract">Y-box binding protein 1 (YB-1) is an imperative biomarker for the clinical out-come of cancer patients. An overexpression of YB-1 in cancerous and adjoining tissues is an indication of aggressiveness and advanced stages. In normal resting cells, YB-1 is localized in cytoplasm while in stress conditions like cancer, nuclear shuttling of YB-1 takes place. In this review, the clinical importance of YB-1 in different cancers and the mechanism behind YB-1 nuclear shuttling have been discussed in detail. Targeted chemotherapies or molecularly targeted drugs of great importance can target and block specific molecules implicated in tumor growth and progression. YB-1 has been considered as a bonafide oncogene and accumulating evidences show the therapeutic importance of YB-1. Therapeutic strategies targeting YB-1 may improve the survival rate in cancer patients. This review extensively discusses the therapeutic importance of YB-1.</p><p> </p>
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Lloberas, J., R. A. Maki, and A. Celada. "Repression of major histocompatibility complex I-A beta gene expression by dbpA and dbpB (mYB-1) proteins." Molecular and Cellular Biology 15, no. 9 (September 1995): 5092–99. http://dx.doi.org/10.1128/mcb.15.9.5092.
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The induction of major histocompatibility complex class II gene expression is mediated by three DNA elements in the promoters of these genes (W, X, and Y boxes). The Y box contains an inverted CCAAT box sequence, and the binding activity to the CAAT box is mediated by factor NF-Y, which is composed of subunits NF-YA and NF-YB. We have found that transfection of either dbpA or dbpB (mYB-1) or both inhibits I-A beta gene expression. Although the genes for some members of the Y-box family of binding proteins have been isolated by screening an expression library using the Y-box sequence, under our conditions no binding of dbpA or dbpB to the Y box of the I-A beta or I-E alpha promoter was detected. This suggested that repression of I-A beta gene expression by dbpA and dbpB was not due to competition for binding to the Y-box sequence. The results suggest two other mechanisms by which dbpA and dbpB can inhibit transcription from the I-A beta promoter. When dbpA was added, the binding of NF-YA to DNA increased, which could be explained by interaction between these two proteins whose purpose is to increase the binding affinity of NF-YA for DNA. However, this complex was unable to stimulate transcription from the I-A beta promoter. Thus, dbpA competed for the interaction between NF-YA and NF-YB by binding to NF-YA. When dbpB factor was added together with NF-YA and NF-YB, the binding of the NF-YA--NF-YB complex was reduced. This suggested that dbpB may complete with NF-YB for interaction with NF-YA. These results provide an example of how dbpA and dbpB may regulate transcription of promoters that utilize NF-Y as a transcription factor.
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Wang, Wei-Ting, Tsung-Yuan Tsai, Chi-Hong Chao, Bo-Ying Lai, and Yan-Hwa Wu Lee. "Y-Box Binding Protein 1 Stabilizes Hepatitis C Virus NS5A via Phosphorylation-Mediated Interaction with NS5A To Regulate Viral Propagation." Journal of Virology 89, no. 22 (September 9, 2015): 11584–602. http://dx.doi.org/10.1128/jvi.01513-15.
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ABSTRACTReplication of hepatitis C virus (HCV) is dependent on virus-encoded proteins and numerous cellular factors. DDX3 is a well-known host cofactor of HCV replication. In this study, we investigated the role of a DDX3-interacting protein, Y-box binding protein 1 (YB-1), in the HCV life cycle. Both YB-1 and DDX3 interacted with the viral nonstructural protein NS5A. During HCV infection, YB-1 partially colocalized with NS5A and the HCV replication intermediate double-stranded RNA (dsRNA) in HCV-infected Huh-7.5.1 cells. Despite sharing the same interacting partners, YB-1 participated in HCV RNA replication but was dispensable in steady-state HCV RNA replication, different from the action of DDX3. Moreover, knockdown of YB-1 in HCV-infected cells prevented infectious virus production and reduced the ratio of hyperphosphorylated (p58) to hypophosphorylated (p56) forms of NS5A, whereas DDX3 silencing did not affect the ratio of the p58 and p56 phosphoforms of NS5A. Interestingly, silencing of YB-1 severely reduced NS5A protein stability in NS5A-ectopically expressing, replicon-containing, and HCV-infected cells. Furthermore, mutations of serine 102 of YB-1 affected both YB-1–NS5A interaction and NS5A-stabilizing activity of YB-1, indicating that this Akt phosphorylation site of YB-1 plays an important role in stabilizing NS5A. Collectively, our results support a model in which the event of YB-1 phosphorylation-mediated interaction with NS5A results in stabilizing NS5A to sustain HCV RNA replication and infectious HCV production. Overall, our study may reveal a new aspect for the development of novel anti-HCV drugs.IMPORTANCEChronic hepatitis C virus (HCV) infection induces liver cirrhosis and hepatocellular carcinoma. The viral nonstructural protein NS5A co-opting various cellular signaling pathways and cofactors to support viral genome replication and virion assembly is a new strategy for anti-HCV drug development. NS5A phosphorylation is believed to modulate switches between different stages of the HCV life cycle. In this study, we identified the cellular protein YB-1 as a novel NS5A-interacting protein. YB-1 is a multifunctional protein participating in oncogenesis and is an oncomarker of hepatocellular carcinoma (HCC). We found that YB-1 protects NS5A from degradation and likely regulates NS5A phosphorylation through its phosphorylation-dependent interaction with NS5A, which might be controlled by HCV-induced signaling pathways. Our observations suggest a model in which HCV modulates NS5A level and the ratio of the p58 and p56 phosphoforms for efficient viral propagation via regulation of cellular signaling inducing YB-1 phosphorylation. Our finding may provide new aspects for developing novel anti-HCV drugs.
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Mehta, Sunali, Michael Algie, Tariq Al-Jabry, Cushla McKinney, Srinivasaraghavan Kannan, Chandra S. Verma, Weini Ma, et al. "Critical Role for Cold Shock Protein YB-1 in Cytokinesis." Cancers 12, no. 9 (September 1, 2020): 2473. http://dx.doi.org/10.3390/cancers12092473.
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High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in immortalized fibroblasts resulted in cytokinesis failure and consequent multinucleation. Rescue experiments indicated that YB-1 was required for completion of cytokinesis. Using confocal imaging we found that YB-1 was essential for orchestrating the spatio-temporal distribution of the microtubules, β-actin and the chromosome passenger complex (CPC) to define the cleavage plane. We show that phosphorylation at six serine residues was essential for cytokinesis, of which novel sites were identified using mass spectrometry. Using atomistic modelling we show how phosphorylation at multiple sites alters YB-1 conformation, allowing it to interact with protein partners. Our results establish phosphorylated YB-1 as a critical regulator of cytokinesis, defining precisely how YB-1 regulates cell division.
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Pise-Masison, C. A., J. Dittmer, K. E. Clemens, and J. N. Brady. "Physical and functional interaction between the human T-cell lymphotropic virus type 1 Tax1 protein and the CCAAT binding protein NF-Y." Molecular and Cellular Biology 17, no. 3 (March 1997): 1236–43. http://dx.doi.org/10.1128/mcb.17.3.1236.
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Tax1, a potent activator of human T-cell lymphotropic virus type 1 (HTLV-1) transcription, has been shown to modulate expression of many cellular genes. Tax1 does not bind DNA directly but regulates transcription through protein-protein interactions with sequence-specific transcription factors. Using the yeast two-hybrid system to screen for proteins which interact with Tax1, we isolated the B subunit of the CCAAT binding protein NF-Y from a HeLa cDNA library. The interaction of Tax1 with NF-YB was specific in that NF-YB did not interact with a variety of other transcription factors, including human immunodeficiency virus Tat, human papillomavirus E6, and Bicoid, or with the M7 (amino acids 29CP-AS) Tax1 mutant. However, NF-YB did interact with the C-terminal Tax1 mutants M22 (130TL-AS) and M47 (319LL-RS). We also show that in vitro-translated NF-YB specifically bound to a glutathione S-transferase-Tax1 fusion protein. Further, Tax1 coimmunoprecipitated with NF-Y from nuclear extracts of HTLV-1-transformed cells, providing evidence for in vivo interaction of Tax1 and NF-YB. We further demonstrate that Tax1 specifically activated the NF-Y-responsive DQbeta promoter, as well as a minimal promoter which contains only the Y-box element. In addition, mutation of the Y-box element alone abrogated Tax1-mediated activation. Taken together, these data indicate that Tax1 interacts with NF-Y through the B subunit and that this interaction results in activation of the major histocompatibility complex class II promoter. Through activation of this and other NF-Y driven promoters, the Tax1-NF-Y interaction may play a critical role in causing cellular transformation and HTLV-1 pathogenesis.
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Ting, J. P., A. Painter, N. J. Zeleznik-Le, G. MacDonald, T. M. Moore, A. Brown, and B. D. Schwartz. "YB-1 DNA-binding protein represses interferon gamma activation of class II major histocompatibility complex genes." Journal of Experimental Medicine 179, no. 5 (May 1, 1994): 1605–11. http://dx.doi.org/10.1084/jem.179.5.1605.
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Interferon gamma (IFN-gamma) is the most potent inducer of class II major histocompatibility complex (MHC) genes. This induction is uniquely mediated by three DNA elements in the promoter region of class II MHC genes. One of these DNA elements, Y, contains an inverted CCAAT box. Previously, we have screened a lambda gt11 library for Y-binding proteins and identified the YB-1 gene. Here we provide evidence that YB-1 can repress the IFN-gamma induction of class II MHC promoter as well as the Invariant chain (Ii) gene which also contains a Y element in its promoter. This was demonstrated by cotransfecting a YB-1 expression vector with promoter-reporter gene constructs. As an alternate approach, an efficient transient transfection system was developed which resulted in a > 70% transfection efficiency. Transfection of YB-1 by this procedure resulted in the near abrogation of IFN-gamma induced HLA-DR antigen and mRNA expression. These findings show the functional suppression of class II MHC gene induction by the YB-1 protein.
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Li, W. W., Y. Hsiung, V. Wong, K. Galvin, Y. Zhou, Y. Shi, and A. S. Lee. "Suppression of grp78 core promoter element-mediated stress induction by the dbpA and dbpB (YB-1) cold shock domain proteins." Molecular and Cellular Biology 17, no. 1 (January 1997): 61–68. http://dx.doi.org/10.1128/mcb.17.1.61.
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The highly conserved grp78 core promoter element plays an important role in the induction of grp78 under diverse stress signals. Previous studies have established a functional region in the 3' half of the core (stress-inducible change region [SICR]) which exhibits stress-inducible changes in stressed nuclei. The human transcription factor YY1 is shown to bind the SICR and transactivate the core element under stress conditions. Here we report that expression library screening with the core element has identified two new core binding proteins, YB-1 and dbpA. Both proteins belong to the Y-box family of proteins characterized by an evolutionarily conserved DNA binding motif, the cold shock domain (CSD). In contrast to YY1, which binds only double-stranded SICR, the Y-box/CSD proteins much prefer the lower strand of the SICR. The Y-box proteins can repress the inducibility of the grp78 core element mediated by treatment of cells with A23187, thapsigargin, and tunicamycin. In gel shift assays, YY1 binding to the core element is inhibited by either YB-1 or dbpA. A yeast interaction trap screen using LexA-YY1 as a bait and a HeLa cell cDNA-acid patch fusion library identified YB-1 as a YY1-interacting protein. In cotransfection experiments, the Y-box proteins antagonize the YY1-mediated enhancement of transcription directed by the grp78 core in stressed cells. Thus, the CSD proteins may be part of the stress signal transduction mechanism in the mammalian system.
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Chatterjee, Manik, Christoph Ransco, Thorsten Stühmer, Niels Eckstein, Hans-Dieter Royer, and Ralf Bargou. "The Y-box Binding Protein YB-1 Is Associated with Progressive Disease and Mediates Survival and Drug Resistance in Multiple Myeloma." Blood 106, no. 11 (November 16, 2005): 3385. http://dx.doi.org/10.1182/blood.v106.11.3385.3385.
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Abstract Introduction: The Y-box binding protein YB-1 is a member of the cold shock domain protein superfamily and represents one of the most evolutionary conserved nucleic-acid binding proteins. Yb-1 is involved in a wide variety of cellular functions, such as regulation of transcription and translation, but also in DNA-repair and stress response to extracellular signals. Furthermore, recent reports from our group could show that overexpressed YB-1 plays a role in drug resistance of breast cancer cells and might act as an oncogene. The goal of this study was to investigate a potential pathogenetic role of YB-1 in MM. Material and Methods: For the detection of YB-1 expression in vivo, bone marrow biopsies of MM patients were analyzed by immunohistochemistry. The expression of YB-1 protein in a number of MM cell lines was analyzed by Western Blotting. The regulation of YB-1 expression through major signaling pathways, e.g. IL-6R/STAT3, Ras/MAPK and PI3K/AKT, was analyzed using specific inhibitors of these pathways (Sant7, PD98059 and Ly294002). To determine the role of YB-1 for survival and proliferation, siRNA technology was exploited to transiently knockdown the expression of YB-1 in the MM cell lines INA-6 and MM.1s. In addition, these YB-1 knockdown cells were exposed to doxorubicin and melphalan to evaluate the influence of YB-1 on drug resistance. Results: Immunohistochemical analyses of bone marrow biopsies revealed that YB-1 is strongly expressed only in MM cells of samples that show a highly proliferative phenotype. This subgroup of MM patients was characterized by an aggressive clinical course. In contrast, MM cells of samples with a slow proliferative status did not show YB-1 expression. Interestingly, tumor cells of patients that responded to chemotherapy did not express YB-1. Furthermore, neither normal bone marrow plasma cells nor premalignant plasma cells of MGUS patients showed YB-1 expression. YB-1 was detected in all of the evaluated MM cell lines. YB-1 expression was not regulated by the IL-6R/STAT3, Ras/MAPK and PI3K/AKT pathways. Knockdown of YB-1 in INA-6 and MM1.s cells by siRNA resulted in a slow proliferation phenotype with a higher apoptotic cell fraction. In addition, we observed that YB-1 knockdown remarkably sensitized cells towards drug-induced apoptosis. Conclusions: YB-1 expression in MM appears to be correlated with a highly proliferative phenotype and with disease progression. YB-1 contributes to the malignant growth and drug resistance and might be therefore an attractive therapeutical target to circumvent aquired drug resistance in MM.
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Tanabe, Yumiko, Satoru Nagatoishi, and Kouhei Tsumoto. "Thermodynamic characterization of the interaction between the human Y-box binding protein YB-1 and nucleic acids." Molecular BioSystems 11, no. 9 (2015): 2441–48. http://dx.doi.org/10.1039/c5mb00184f.
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Tiwari, Aadhya, Mari Iida, Corinna Kosnopfel, Mahyar Abbariki, Apostolos Menegakis, Birgit Fehrenbacher, Julia Maier, et al. "Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers." Cancers 12, no. 10 (September 29, 2020): 2795. http://dx.doi.org/10.3390/cancers12102795.
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The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.
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Sobočan, Monika, Suzana Bračič, Jure Knez, Iztok Takač, and Johannes Haybaeck. "The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer." Cancers 12, no. 1 (January 14, 2020): 205. http://dx.doi.org/10.3390/cancers12010205.
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Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.
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Kretov, Dmitry A., Daria A. Mordovkina, Irina A. Eliseeva, Dmitry N. Lyabin, Dmitry N. Polyakov, Vandana Joshi, Bénédicte Desforges, et al. "Inhibition of Transcription Induces Phosphorylation of YB-1 at Ser102 and Its Accumulation in the Nucleus." Cells 9, no. 1 (December 31, 2019): 104. http://dx.doi.org/10.3390/cells9010104.
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The Y-box binding protein 1 (YB-1) is an RNA/DNA-binding protein regulating gene expression in the cytoplasm and the nucleus. Although mostly cytoplasmic, YB-1 accumulates in the nucleus under stress conditions. Its nuclear localization is associated with aggressiveness and multidrug resistance of cancer cells, which makes the understanding of the regulatory mechanisms of YB-1 subcellular distribution essential. Here, we report that inhibition of RNA polymerase II (RNAPII) activity results in the nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102. The inhibition of kinase activity reduces YB-1 phosphorylation and its accumulation in the nucleus. The presence of RNA in the nucleus is shown to be required for the nuclear retention of YB-1. Thus, the subcellular localization of YB-1 depends on its post-translational modifications (PTMs) and intracellular RNA distribution.
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Somasekharan, Syam Prakash, Amal El-Naggar, Gabriel Leprivier, Hongwei Cheng, Shamil Hajee, Thomas G. P. Grunewald, Fan Zhang, et al. "YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1." Journal of Cell Biology 208, no. 7 (March 23, 2015): 913–29. http://dx.doi.org/10.1083/jcb.201411047.
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Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5′ untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression.
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Lyabin, Dmitry N., Irina A. Eliseeva, Olga V. Skabkina, and Lev P. Ovchinnikov. "Interplay between Y-box-binding protein 1 (YB-1) and poly(A) binding protein (PABP) in specific regulation ofYB-1mRNA translation." RNA Biology 8, no. 5 (September 2011): 883–92. http://dx.doi.org/10.4161/rna.8.5.16022.
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Ashizuka, Megumi, Takao Fukuda, Takanori Nakamura, Kanemitsu Shirasuna, Kazuhiro Iwai, Hiroto Izumi, Kimitoshi Kohno, Michihiko Kuwano, and Takeshi Uchiumi. "Novel Translational Control through an Iron-Responsive Element by Interaction of Multifunctional Protein YB-1 and IRP2." Molecular and Cellular Biology 22, no. 18 (September 15, 2002): 6375–83. http://dx.doi.org/10.1128/mcb.22.18.6375-6383.2002.
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ABSTRACT The eukaryotic Y-box-binding protein YB-1 functions in various biological processes, including DNA repair, cell proliferation, and transcriptional and translational controls. To gain further insight into how human YB-1 plays its role in pleiotropic functions, we here used two-hybrid screenings to identify partners of this protein; the results showed that YB-1 itself, iron-regulatory protein 2 (IRP2), and five ribosomal proteins each served as partners to YB-1. We then examined the biological effect of the interaction of YB-1 and IRP2 on translational regulation. Both in vitro binding and coimmunoprecipitation assays showed the direct interaction of YB-1 and IRP2 in the presence of a high concentration of iron. RNA gel shift assays showed that YB-1 reduced the formation of the IRP2-mRNA complex when the iron-responsive element of the ferritin mRNA 5′ untranslated region (UTR) was used as a probe. By using an in vitro translation assay using luciferase mRNA ligated to the ferritin mRNA 5′UTR as a reporter construct, we showed that both YB-1 and IRP2 inhibited the translation of the mRNA. However, coadministration of YB-1 and IRP2 proteins abrogated the inhibition of protein synthesis by each protein. An In vivo coimmunoprecipitation assay showed that IRP2 bound to YB-1 in the presence of iron and a proteasome inhibitor. The direct interaction of YB-1 and IRP2 provides the first evidence of the involvement of YB-1 in the translational regulation of an iron-related protein.
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Fomina, E. E., P. E. Pestryakov, E. A. Maltseva, I. O. Petruseva, D. A. Kretov, L. P. Ovchinnikov, and O. I. Lavrik. "Y-box binding protein 1 (YB-1) promotes detection of DNA bulky lesions by XPC-HR23B factor." Biochemistry (Moscow) 80, no. 2 (February 2015): 219–27. http://dx.doi.org/10.1134/s000629791502008x.
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Maier, Attenberger, Tiwari, Lettau, Rebholz, Fehrenbacher, Schaller, Gani, and Toulany. "Dual Targeting of Y-Box Binding Protein-1 and Akt Inhibits Proliferation and Enhances the Chemosensitivity of Colorectal Cancer Cells." Cancers 11, no. 4 (April 19, 2019): 562. http://dx.doi.org/10.3390/cancers11040562.
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KRAS-mutated colorectal cancers (CRCs) are resistant to cetuximab treatment. The multifunctional Y-box binding protein 1 (YB-1) is overexpressed in CRC and is associated with chemoresistance. In this study, the effects of oncogenic mutated KRAS(G12V) and KRAS(G13D) on YB-1 phosphorylation were investigated in CRC cells. The effects of the inhibition of p90 ribosomal S6 kinase (RSK) on YB-1 phosphorylation, cell proliferation and survival were tested with and without treatment with 5-fluorouracil using pharmacological inhibitors and siRNA. YB-1 phosphorylation status and subcellular distribution in CRC patient tissues were determined by immunofluorescence staining and confocal microscopy. Endogenous expression of mutated KRAS(G13D) and conditional expression of KRAS(G12V) significantly stimulated YB-1 phosphorylation via RSK and were associated with cetuximab resistance. Inhibition of YB-1 by targeting RSK stimulated the Akt signaling pathway, and this stimulation occurred independently of KRAS mutational status. Akt activation interfered with the antiproliferative effect of the RSK inhibitor. Consequently, dual targeting of RSK and Akt efficiently inhibited cell proliferation in KRAS(G13D)-mutated HCT116 and KRAS wild-type SW48 cells. Treatment with 5-fluorouracil (5-FU) significantly enhanced YB-1 phosphorylation in KRAS(G13D)-mutated HCT116 cells but not in KRAS wild-type SW48 cells. Dual targeting of Akt and RSK sensitized HCT116 cells to 5-FU by stimulating 5-FU-induced apoptosis and inhibiting repair of 5-FU-induced DNA damage. YB-1 was highly phosphorylated in CRC patient tumor tissues and was mainly localized in the nucleus. Together, dual targeting of RSK and Akt may be an alternative molecular targeting approach to cetuximab for treating CRC in which YB-1 is highly phosphorylated.
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Astanehe, Arezoo, Melanie Finkbeiner, Karen To, and Sandra E. Dunn. "THE TRANSCRIPTION FACTOR Y-BOX BINDING PROTEIN-1 (YB-1) INDUCES EXPRESSION OF THE PIK3CA ONCOGENE LEADING TO INCREASED INVASION OFBASAL-LIKE BREAST CARCINOMA CELLS." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 3. http://dx.doi.org/10.25011/cim.v31i4.4788.
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Background: Basal-like breast carcinoma (BLBC) is the mostaggressive subtype of breast cancer. 73% of BLBC over-express YB-1, anoncogenic transcription/translation factor. PIK3CA, which codes for the p110? catalytic subunit ofphosphatidylinositol-3-kinase (PI3K), is another oncogene. The PI3K signalling pathway is fundamental in the regulation of many cellular functions and isoften deregulated in cancer. Despite its importance, the knowledge on the transcriptional regulation of PIK3CA is limited. Indeed, we have recently published the first report on the PIK3CA promoter. Methods and Results: A genome-wide chromatin immunoprecipitation on chip (ChIP-on-chip) analysis of a BLBC cell-line(SUM149) suggested binding of YB-1 to the PIK3CA promoter. This binding was verified using traditional chromatin immunoprecipitation (ChIP). Furthermore, electrophoretic mobility shift assay (EMSA) using oligonucleotides with eitherwild-type or mutated YB-1 responsive elements mapped YB-1 binding to three sites on the PIK3CA promoter. Silencing YB-1 in BLBC cell-lines (SUM149, HCC1937, andMDA-MB-231) decreased, while over-expression of YB-1 increased the PIK3CA promoter activity, transcript, and protein levels. Interestingly, array comparative genomic hybridization(aCGH) and quantitative PCR demonstrated PIK3CA copy number gains in HCC1937 andMDA-MB-231 cells. Although PIK3CA amplifications are overall uncommon (9%) in breast cancer, we demonstrated here that low level gains in PIK3CA copy number are present in 30%of primary BLBC cases. Furthermore, it has previously been demonstrated that mutations of PIK3CA are the most common genetic aberration (27%) found in breast cancer. These mutations lead to constitutive activation of p110? and are highly oncogenic. Over-expression of YB-1in MCF-7 cells, which harbour an activating PIK3CA mutation, increased PIK3CA transcript and protein levels. Furthermore, induction of PIK3CA by YB-1 leads to increased levels of urokinase plasminogenactivator (uPA) and invasion. Conclusions: Our data demonstrates that YB-1 binds to the PIK3CA promoter and induces itsexpression whether the gene is wild-type or amplified. Moreover, since YB-1induces expression of the active mutant p110?, then therapeutic inhibition of YB-1 may lead to decreased p110? and interference with the constitutively activated PI3K pathway in cancers. In addition, the YB-1/PIK3CA/uPA network provides information regarding the possible therapeutic targets for prevention of breast cancer invasion and metastasis. A.A. is supported by a Child and Family–CIHR–UBC MD/PhD Studentship Award.
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Taylor, Louisa, Ian Kerr, and Beth Coyle. "MBRS-42. YB-1 - A NOVEL THERAPEUTIC TARGET IN HIGH-RISK MEDULLOBLASTOMA?" Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii405. http://dx.doi.org/10.1093/neuonc/noaa222.551.
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Abstract Medulloblastoma relapse occurs in 30–40% of patients and is typically fatal. The emergence of therapy resistant sub-clones likely plays a major role in a large proportion of recurrent medulloblastoma. Y-box binding protein 1 (YB-1) is a multifunctional transcription/translation factor and known onco-protein. Overexpression has been described in numerous cancers, where elevated expression and nuclear accumulation correlates with disease progression, metastasis and drug resistance. Genomic analysis of a large medulloblastoma cohort revealed YB-1 up-regulation across all subgroups of medulloblastoma, where elevated expression correlated with poor survival. Immunohistochemical staining of patient tissue microarrays displayed significant YB-1 expression, with a high proportion (83%) of patients exhibiting nuclear accumulation. High YB-1 expression was also observed at both protein and RNA level across medulloblastoma cell lines, with expression highest in Group 3 and 4. Hence, we hypothesised that YB-1 plays a role in medulloblastoma chemoresistance and progression. Treatment of Group 3 (HDMB-03 and D283MED) and SHH (DAOY) cell lines with vincristine and cisplatin and analysis of cellular localisation by nuclear/cytoplasmic fractionation and immunofluorescence demonstrated that YB-1 undergoes nuclear translocation in response to these standard medulloblastoma chemotherapy agents. Chromatin immunoprecipitation (ChIP) analysis of untreated Group 3 cell lines (D283MED and HDMB-03) demonstrated considerable YB-1 interaction with an inverted CCAAT box in the ATP-binding cassette subfamily B member 1 (ABCB1) promoter. RT-PCR analysis of ABCB1 following vincristine and cisplatin treatment revealed differences in transcript expression, indicative of different YB-1 promoter interactions dependent on chemotherapeutic treatment. Our results highlight YB-1 as a novel candidate chemoresistance driver in medulloblastoma.
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Chatterjee, Manik, Christoph Rancso, Thorsten Stühmer, Niels Eckstein, Mindaugas Andrulis, Christian Gerecke, Heike Lorentz, Hans-Dieter Royer, and Ralf C. Bargou. "The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma." Blood 111, no. 7 (April 1, 2008): 3714–22. http://dx.doi.org/10.1182/blood-2007-05-089151.
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Abstract Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y-box binding protein YB-1 in MM. YB-1 is a member of the cold-shock domain protein superfamily and involved in various cellular functions such as proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS), nor MM cells with a mature morphology showed expression of YB-1 in situ. In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1–expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced apoptosis in MM cells even in the presence of BM stromal cells. Furthermore, we found that overexpression of YB-1 mediated resistance toward doxorubicin-induced apoptosis in MM cells. Thus, YB-1 contributes to disease progression, survival, and drug resistance in MM and might therefore provide an attractive therapeutic target.
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Lasham, Annette, Cristin G. Print, Adele G. Woolley, Sandra E. Dunn, and Antony W. Braithwaite. "YB-1: oncoprotein, prognostic marker and therapeutic target?" Biochemical Journal 449, no. 1 (December 7, 2012): 11–23. http://dx.doi.org/10.1042/bj20121323.
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Hanahan and Weinberg have proposed the ‘hallmarks of cancer’ to cover the biological changes required for the development and persistence of tumours [Hanahan and Weinberg (2011) Cell 144, 646–674]. We have noted that many of these cancer hallmarks are facilitated by the multifunctional protein YB-1 (Y-box-binding protein 1). In the present review we evaluate the literature and show how YB-1 modulates/regulates cellular signalling pathways within each of these hallmarks. For example, we describe how YB-1 regulates multiple proliferation pathways, overrides cell-cycle check points, promotes replicative immortality and genomic instability, may regulate angiogenesis, has a role in invasion and metastasis, and promotes inflammation. We also argue that there is strong and sufficient evidence to suggest that YB-1 is an excellent molecular marker of cancer progression that could be used in the clinic, and that YB-1 could be a useful target for cancer therapy.
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Nishio, Shin, Kimio Ushijima, Shuji Takemoto, Yuko Sasajima, Hitoshi Tsuda, Takahiro Kasamatsu, and Toshiharu Kamura. "Nuclear Y-box binding protein-1 expression as a prognostic marker and correlation with epidermal growth factor receptor expression in cervical cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 5085. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.5085.
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5085 Background: Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many reports indicate that YB-1 is highly expressed in tumor cells and is a marker of tumor aggressiveness and clinical prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been associated with poor outcomes in cervical cancer (CC). Clinical trials have shown that EGFR inhibitors are effective against CC (JCO 2011). Nuclear YB-1 expression correlates with EGFR expression in various types of cancer. Methods: Nuclear YB-1 expression was immunohistochemically analyzed in tissue specimens obtained from 204 CC patients who underwent surgery. Associations of nuclear YB-1 expression with clinicopathological factors such as survival and EGFR (HER1 and HER2) expression were investigated. Results: Nuclear YB-1 expression was observed in 41 (20%) of 204 cases and correlated with stage, tumor diameter, stromal invasion, and lymph-node metastasis. Nuclear YB-1 expression also correlated with both HER1 expression (p=0.0114) and HER2 expression (p=0.0053). Kaplan-Meier survival analysis showed that nuclear YB-1 expression was significantly associated with poor outcomes in terms of progression-free survival (p=0.0033) and overall survival (p=0.0003). On multivariate analysis, stromal invasion, parametrial invasion, and nuclear YB-1 expression were independent predictors of survival. Conclusions: Nuclear YB-1 expression is a prognostic marker and correlates with EGFR expression in CC.
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Grant, C. E., and R. G. Deeley. "Cloning and characterization of chicken YB-1: regulation of expression in the liver." Molecular and Cellular Biology 13, no. 7 (July 1993): 4186–96. http://dx.doi.org/10.1128/mcb.13.7.4186.
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A cDNA expression library constructed from day 9 embryonic liver was screened with a previously identified protein binding site in the flanking region of the liver-specific, estrogen-dependent avian apoVLDLII gene. Two of the clones isolated were shown to encode the chicken homolog of the Y-box binding protein, YB-1 (dbpb), which we have designated chkYB-1. This protein was originally identified in avian extracts by virtue of its ability to bind to two reverse CCAAT motifs in the Rous sarcoma virus enhancer. Since its identification, additional nucleic acid binding properties have been ascribed to its homologs, or closely related proteins, in other species. We have determined the sequence of chkYB-1, investigated its ability to bind to sites known to be involved in tissue-specific expression in the liver, and examined factors influencing its hepatic expression. These studies have demonstrated that the level of chkYB-1 mRNA in the liver decreases steadily throughout embryogenesis and for several weeks posthatching until adult levels are attained. We present several lines of evidence that YB-1 expression in the liver is positively associated with DNA synthesis or cell proliferation. Its binding characteristics indicate that the protein can interact specifically with a number of binding sites for liver-enriched or specific factors. In addition, although it is not particularly asymmetric in terms of base composition, we find a marked preference in binding to the pyrimidine-rich strand of these sites regardless of the presence or polarity of an intact CCAAT box. The increased levels of expression of YB-1 during proliferation combined with its binding characteristics suggest that it may be involved in the reduced expression of liver-specific genes observed at early stages of development or during liver regeneration.
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Grant, C. E., and R. G. Deeley. "Cloning and characterization of chicken YB-1: regulation of expression in the liver." Molecular and Cellular Biology 13, no. 7 (July 1993): 4186–96. http://dx.doi.org/10.1128/mcb.13.7.4186-4196.1993.
Full textAbstract:
A cDNA expression library constructed from day 9 embryonic liver was screened with a previously identified protein binding site in the flanking region of the liver-specific, estrogen-dependent avian apoVLDLII gene. Two of the clones isolated were shown to encode the chicken homolog of the Y-box binding protein, YB-1 (dbpb), which we have designated chkYB-1. This protein was originally identified in avian extracts by virtue of its ability to bind to two reverse CCAAT motifs in the Rous sarcoma virus enhancer. Since its identification, additional nucleic acid binding properties have been ascribed to its homologs, or closely related proteins, in other species. We have determined the sequence of chkYB-1, investigated its ability to bind to sites known to be involved in tissue-specific expression in the liver, and examined factors influencing its hepatic expression. These studies have demonstrated that the level of chkYB-1 mRNA in the liver decreases steadily throughout embryogenesis and for several weeks posthatching until adult levels are attained. We present several lines of evidence that YB-1 expression in the liver is positively associated with DNA synthesis or cell proliferation. Its binding characteristics indicate that the protein can interact specifically with a number of binding sites for liver-enriched or specific factors. In addition, although it is not particularly asymmetric in terms of base composition, we find a marked preference in binding to the pyrimidine-rich strand of these sites regardless of the presence or polarity of an intact CCAAT box. The increased levels of expression of YB-1 during proliferation combined with its binding characteristics suggest that it may be involved in the reduced expression of liver-specific genes observed at early stages of development or during liver regeneration.
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Makino, Y. "Structural and functional analysis of the human Y-box binding protein (YB-1) gene promoter." Nucleic Acids Research 24, no. 10 (May 15, 1996): 1873–78. http://dx.doi.org/10.1093/nar/24.10.1873.
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Gong, Huilin, Shan Gao, Chenghuan Yu, Meihe Li, Ping Liu, Guanjun Zhang, Jinning Song, and Jin Zheng. "Effect and mechanism of YB-1 knockdown on glioma cell growth, migration, and apoptosis." Acta Biochimica et Biophysica Sinica 52, no. 2 (February 2020): 168–79. http://dx.doi.org/10.1093/abbs/gmz161.
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Abstract Y-box binding protein 1 (YB-1) is manifested as its involvement in cell proliferation and differentiation and malignant cell transformation. Overexpression of YB-1 is associated with glioma progression and patient survival. The aim of this study is to investigate the influence of YB-1 knockdown on glioma cell progression and reveal the mechanisms of YB-1 knockdown on glioma cell growth, migration, and apoptosis. It was found that the knockdown of YB-1 decreased the mRNA and protein levels of YB-1 in U251 glioma cells. The knockdown of YB-1 significantly inhibited cell proliferation, colony formation, and migration in vitro and tumor growth in vivo. Proteome and phosphoproteome data revealed that YB-1 is involved in glioma progression through regulating the expression and phosphorylation of major proteins involved in cell cycle, adhesion, and apoptosis. The main regulated proteins included CCNB1, CCNDBP1, CDK2, CDK3, ADGRG1, CDH-2, MMP14, AIFM1, HO-1, and BAX. Furthermore, it was also found that YB-1 knockdown is associated with the hypo-phosphorylation of ErbB, mTOR, HIF-1, cGMP-PKG, and insulin signaling pathways, and proteoglycans in cancer. Our findings indicated that YB-1 plays a key role in glioma progression in multiple ways, including regulating the expression and phosphorylation of major proteins associated with cell cycle, adhesion, and apoptosis.
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Sangermano, Felicia, Antonella Delicato, and Viola Calabrò. "Y box binding protein 1 (YB-1) oncoprotein at the hub of DNA proliferation, damage and cancer progression." Biochimie 179 (December 2020): 205–16. http://dx.doi.org/10.1016/j.biochi.2020.10.004.
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Li, Fei, Zhenzeng Ma, Heng Liu, Qidi Zhang, Xiaobo Cai, Ying Qu, Mingyi Xu, and Lungen Lu. "Y-box Protein-1 Regulates the Expression of Collagen I in Hepatic Progenitor Cells via PDGFR-β/ERK/p90RSK Signalling." Stem Cells International 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/6193106.
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Y-box protein-1 (YB-1) is a highly conserved transcription factor that is involved in multiple biological processes via transcriptional regulation of several genes, including p53, cyclin D1, and EGFR. YB-1 has been reported to be overexpressed in injured livers. This study aims to explore the functions of YB-1 in hepatic progenitor cells (HPCs). Herein, chromatin immunoprecipitation sequencing (ChIP-sequencing) and RNA-sequencing assays identified that YB-1 participated in the biological adhesion process and ECM-receptor interactions in HPCs. Further study demonstrated that YB-1 modulated the expression of extracellular matrix components in HPCs. ChIP-sequencing assays established that PDGFR-β was a target gene of YB-1, and luciferase reporter assays confirmed that YB-1 negatively regulated PDGFR-β promoter activity in HPCs. In addition, PDGFR-β can regulate the expression of collagen I through ERK/p90RSK signalling, and disruption of the signalling pathway with a PDGFR-β inhibitor or ERK1/2 inhibitor abolished the regulatory effect of PDGFR-β on collagen I expression in HPCs. Conclusively, YB-1 can modulate the expression of collagen I in HPCs via direct binding to the PDGFR-β promoter, negatively regulating its expression. In addition, the ERK/p90RSK axis serves as the downstream signalling pathway of PDGFR-β.
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Dong, Jinjiang, Argun Akcakanat, David N. Stivers, Jiexin Zhang, Doyil Kim, and Funda Meric-Bernstam. "RNA-binding specificity of Y-box protein 1." RNA Biology 6, no. 1 (January 2009): 59–64. http://dx.doi.org/10.4161/rna.6.1.7458.
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Hessman, Christopher L., Josephine Hildebrandt, Aneri Shah, Sabine Brandt, Antonia Bock, Björn C. Frye, Ute Raffetseder, et al. "YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling." International Journal of Molecular Sciences 21, no. 19 (September 25, 2020): 7076. http://dx.doi.org/10.3390/ijms21197076.
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Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.
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Kosnopfel, Corinna, Tobias Sinnberg, Birgit Sauer, Heike Niessner, Alina Muenchow, Birgit Fehrenbacher, Martin Schaller, et al. "Tumour Progression Stage-Dependent Secretion of YB-1 Stimulates Melanoma Cell Migration and Invasion." Cancers 12, no. 8 (August 18, 2020): 2328. http://dx.doi.org/10.3390/cancers12082328.
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Secreted factors play an important role in intercellular communication. Therefore, they are not only indispensable for the regulation of various physiological processes but can also decisively advance the development and progression of tumours. In the context of inflammatory disease, Y-box binding protein 1 (YB-1) is actively secreted and the extracellular protein promotes cell proliferation and migration. In malignant melanoma, intracellular YB-1 expression increases during melanoma progression and represents an unfavourable prognostic marker. Here, we show active secretion of YB-1 from melanoma cells as opposed to benign cells of the skin. Intriguingly, YB-1 secretion correlates with the stage of melanoma progression and depends on a calcium- and ATP-dependent non-classical secretory pathway leading to the occurrence of YB-1 in the extracellular space as a free protein. Along with an elevated YB-1 secretion of melanoma cells in the metastatic growth phase, extracellular YB-1 exerts a stimulating effect on melanoma cell migration, invasion, and tumourigenicity. Collectively, these data suggest that secreted YB-1 plays a functional role in melanoma cell biology, stimulating metastasis, and may serve as a novel biomarker in malignant melanoma that reflects tumour aggressiveness.
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Guarino, Andrea Maria, Annaelena Troiano, Elio Pizzo, Andrea Bosso, Maria Vivo, Gabriella Pinto, Angela Amoresano, Alessandra Pollice, Girolama La Mantia, and Viola Calabrò. "Oxidative Stress Causes Enhanced Secretion of YB-1 Protein that Restrains Proliferation of Receiving Cells." Genes 9, no. 10 (October 22, 2018): 513. http://dx.doi.org/10.3390/genes9100513.
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The prototype cold-shock Y-box binding protein 1 (YB-1) is a multifunctional protein that regulates a variety of fundamental biological processes including cell proliferation and migration, DNA damage, matrix protein synthesis and chemotaxis. The plethora of functions assigned to YB-1 is strictly dependent on its subcellular localization. In resting cells, YB-1 localizes to cytoplasm where it is a component of messenger ribonucleoprotein particles. Under stress conditions, YB-1 contributes to the formation of stress granules (SGs), cytoplasmic foci where untranslated messenger RNAs (mRNAs) are sorted or processed for reinitiation, degradation, or packaging into ribonucleoprotein particles (mRNPs). Following DNA damage, YB-1 translocates to the nucleus and participates in DNA repair thereby enhancing cell survival. Recent data show that YB-1 can also be secreted and YB-1-derived polypeptides are found in plasma of patients with sepsis and malignancies. Here we show that in response to oxidative insults, YB-1 assembly in SGs is associated with an enhancement of YB-1 protein secretion. An enriched fraction of extracellular YB-1 (exYB-1) significantly inhibited proliferation of receiving cells and such inhibition was associated to a G2/M cell cycle arrest, induction of p21WAF and reduction of Np63 protein level. All together, these data show that acute oxidative stress causes sustained release of YB-1 as a paracrine/autocrine signal that stimulate cell cycle arrest.
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Mihashi, Hiroyuki. "Histopathological Investigation of Nuclear Y-box Binding Protein-1 Expression in Salivary Gland Carcinoma." Practica Oto-Rhino-Laryngologica 109, no. 5 (2016): 349–59. http://dx.doi.org/10.5631/jibirin.109.349.
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