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Academic literature on the topic 'PHD Knockdown'
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Journal articles on the topic "PHD Knockdown"
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Schultz, Kelly, Vanishree Murthy, Jeffrey B. Tatro та Debbie Beasley. "Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia-inducible factor-1α-dependent mechanisms". American Journal of Physiology-Lung Cellular and Molecular Physiology 296, № 6 (2009): L921—L927. http://dx.doi.org/10.1152/ajplung.90393.2008.
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Arterial O2 levels are thought to modulate vascular smooth muscle cell (VSMC) proliferation and vascular remodeling, but the mechanisms involved are poorly understood. Here, we tested the hypothesis that PHD2, a prolyl hydroxylase domain (PHD)-containing O2 sensor, modulates growth factor-induced proliferative responses of human pulmonary artery SMC (HPASMC). We found that both PHD1 and PHD2 were robustly expressed by HPASMC, and inhibiting prolyl hydroxylase activity pharmacologically by using the nonselective dioxygenase inhibitor dimethyloxalylglycine (DMOG) inhibited proliferation and cyclin A expression induced by PDGF-AB or FGF-2. Specific knockdown of PHD2 using small interfering RNAs had similar effects. The inhibitory effects of DMOG and PHD2 knockdown on proliferation and cyclin A expression were seen under both normoxic (20% O2) and moderately hypoxic (5% O2) conditions, and PHD2 expression was not affected by O2 level nor by stimulation with PDGF or FGF-2, indicating that the proproliferative influence of PHD2 does not involve alterations of its expression. Knockdown of PHD2 increased hypoxia-inducible factor (HIF)-1α expression, as expected, but we also found that HIF-1α knockdown abolished the inhibitory effect of PHD2 knockdown on PDGF-induced cyclin A expression. Therefore, we conclude that PHD2 promotes growth factor-induced responses of human VSMC, acting by HIF-1α-dependent mechanisms. Given the role of PHD2 as an oxygen sensor in mammalian cells, these results raise the possibility that PHD2 links VSMC proliferation to O2 availability.
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Zacharias, Niki M., Lei Wang, Tapati Maity, et al. "Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo." International Journal of Molecular Sciences 22, no. 6 (2021): 2849. http://dx.doi.org/10.3390/ijms22062849.
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Von Hippel Lindau (VHL) inactivation, which is common in clear cell renal cell carcinoma (ccRCC), leads directly to the disruption of oxygen homoeostasis. VHL works through hypoxia-inducible factors (HIFs). Within this VHL-HIF system, prolyl hydroxylases (PHDs) are the intermediary proteins that initiate the degradation of HIFs. PHD isoform 3′s (PHD3) role in ccRCC growth in vivo is poorly understood. Using viral transduction, we knocked down the expression of PHD3 in the human ccRCC cell line UMRC3. Compared with control cells transduced with scrambled vector (UMRC3-SC cells), PHD3-knockdown cells (UMRC3-PHD3KD cells) showed increased cell invasion, tumor growth, and response to sunitinib. PHD3 knockdown reduced HIF2α expression and increased phosphorylated epidermal growth factor (EGFR) expression in untreated tumor models. However, following sunitinib treatment, expression of HIF2α and phosphorylated EGFR were equivalent in both PHD3 knockdown and control tumors. PHD3 knockdown changed the overall redox state of the cell as seen by the increased concentration of glutathione in PHD3 knockdown tumors relative to control tumors. UMRC3-PHD3KD cells had increased proliferation in cell culture when grown in the presence of hydrogen peroxide compared to UMRC3-SC control cells. Our findings illustrate (1) the variable effect of PHD3 on HIF2α expression, (2) an inverse relationship between PHD3 expression and tumor growth in ccRCC animal models, and (3) the role of PHD3 in maintaining the redox state of UMRC3 cells and their proliferative rate under oxidative stress.
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Gu, Wei, Yutong Cheng, Su Wang, Tao Sun, and Zhizhong Li. "PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2." Cardiovascular Toxicology 21, no. 6 (2021): 451–61. http://dx.doi.org/10.1007/s12012-021-09639-0.
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AbstractEpigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.
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Xing, Weirong, Sheila Pourteymoor, and Subburaman Mohan. "Ascorbic acid regulates osterix expression in osteoblasts by activation of prolyl hydroxylase and ubiquitination-mediated proteosomal degradation pathway." Physiological Genomics 43, no. 12 (2011): 749–57. http://dx.doi.org/10.1152/physiolgenomics.00229.2010.
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Mouse genetic studies reveal that ascorbic acid (AA) is essential for osteoblast (OB) differentiation and that osterix (Osx) was a key downstream target of AA action in OBs. To determine the molecular pathways for AA regulation of Osx expression, we evaluated if AA regulates Osx expression by regulating production and/or actions of local growth factors and extracellular matrix (ECM) proteins. Inhibition of actions of IGFs by inhibitory IGFBP-4, BMPs by noggin, and ECM-mediated integrin signaling by RGD did not block AA effects on Osx expression in OBs. Furthermore, blockade of components of MAPK signaling pathway had no effect on AA-induced Osx expression. Because AA is required for prolyl hydroxylase domain (PHD) activity and because PHD-induced prolyl-hydroxylation targets proteins to proteosomal degradation, we next tested if AA effect on Osx expression involves activation of PHD to hydroxylate and induce ubiquitin-proteosome-mediated degradation of transcriptional repressor(s) of Osx gene. Treatment of OBs with dimethyloxallyl glycine and ethyl 3, 4-dihydroxybenzoate, known inhibitors of PHD, completely blocked AA effect on Osx expression and OB differentiation. Knockdown of PHD2 expression by Lentivirus-mediated shRNA abolished AA-induced Osx induction and alkaline phosphatase activity. Furthermore, treatment of OBs with MG115, inhibitor of proteosomal degradation, completely blocked AA effects on Osx expression. Based on these data, we conclude that AA effect on Osx expression is mediated via a novel mechanism that involves PHD2 and proteosomal degradation of a yet to be identified transcriptional repressor that is independent of BMP, IGF-I, or integrin-mediated signaling in mouse OBs.
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Melekhova, Anna, Mirjam Leeder, Thanakorn Pungsrinont, et al. "A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells." Biomolecules 11, no. 8 (2021): 1152. http://dx.doi.org/10.3390/biom11081152.
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Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the other hand, ING3 levels positively correlate with poor survival prognosis of prostate cancer (PCa) patients. In PCa cells, ING3 acts rather as an androgen receptor (AR) co-activator and harbours oncogenic properties in PCa. Here, we show the identification of a novel ING3 splice variant in both the human PCa cell line LNCaP and in human PCa patient specimen. The novel ING3 splice variant lacks exon 11, ING3∆ex11, which results in deletion of the PHD, providing a unique opportunity to analyse functionally the PHD of ING3 by a natural splice variant. Functionally, overexpression of ING3Δex11 induced morphological changes of LNCaP-derived 3D spheroids with generation of lumen and pore-like structures within spheroids. Since these structures are an indicator of epithelial–mesenchymal transition (EMT), key regulatory factors and markers for EMT were analysed. The data suggest that in contrast to ING3, ING3Δex11 specifically modulates the expression of key EMT-regulating upstream transcription factors and induces the expression of EMT markers, indicating that the PHD of ING3 inhibits EMT. In line with this, ING3 knockdown also induced the expression of EMT markers, confirming the impact of ING3 on EMT regulation. Further, ING3 knockdown induced cellular senescence via a pathway leading to cell cycle arrest, indicating an oncogenic role for ING3 in PCa. Thus, the data suggest that the ING3Δex11 splice variant lacking functional PHD exhibits oncogenic characteristics through triggering EMT in PCa cells.
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Querbes, William, Roman Bogorad, Javid Moslehi, et al. "Liver Specific Delivery of siRNA Targeting EGLN Prolyl Hydroxylases Activates Hepatic Erythropoietin Production and Stimulates Erythropoiesis,." Blood 118, no. 21 (2011): 3161. http://dx.doi.org/10.1182/blood.v118.21.3161.3161.
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Abstract Abstract 3161 Anemia in chronic kidney disease patients due to impaired renal production of erythropoietin (EPO) and insufficient erythropoiesis is a significant public health problem. One approach to compensate for the low EPO levels in patients with impaired kidney function would be to stimulate the levels of EPO production from non-renal sources. It is well known that during fetal development the liver serves as the primary producer of EPO until the kidney becomes the dominant source after birth. Negative regulation of EPO production is mediated by the EGLN family of prolyl hydroxylases (PHDs1-3) that play an important role in oxygen sensing by targeting the transcription factor hypoxia inducible factor (HIF) for degradation via the proteasome. HIF stabilization and activity is required to mediate EPO gene transcription. Previously it has been shown that liver specific conditional knockout of all three PHDs is required to activate HIF and induce EPO production in liver (Minamishima et al. Science 2010). Here we show that simultaneous siRNA mediated knockdown of all 3 PHD genes in mouse liver using lipid nanoparticles (LNPs) can induce hepatic EPO mRNA activation, elevation of serum EPO levels and stimulation of erythropoiesis. We extend these data by examining siRNA knockdown of different combinations of the 3 PHD genes and demonstrate that PHD2 is the dominant PHD gene regulating hepatic EPO production. In addition, due to the specificity of the LNP delivery system we show that the HIF activation and increase in EPO mRNA occurs specifically in liver. Increases in serum EPO and hematocrit were durable for two weeks and one month after a single intravenous dose of LNP siRNA. Furthermore, PHD siRNA silencing in a 5/6 nephrectomy model successfully elevates hemoglobin levels and corrects anemia. In conclusion, targeting of EGLN prolyl hydroxylase genes with siRNA therapeutics has potential in the treatment of anemia associated with chronic kidney disease and provides liver-specific target gene regulation. Disclosures: Querbes: Alnylam Pharmaceuticals: Employment. Bogorad:Alnylam Pharmaceuticals: Research Funding. Moslehi:Alnylam Pharmaceuticals: Honoraria. Akinc:Alnylam Pharmaceuticals: Employment. Wong:Alnylam Pharmaceuticals: Employment. Zurenko:Alnylam Pharmaceuticals: Employment. Qin:Alnylam Pharmaceuticals: Employment. Hettinger:Alnylam Pharmaceuticals, Inc.: Employment. Kuchimanchi:Alnylam Pharmaceuticals: Employment. Charisse:Alnylam Pharmaceuticals: Employment. Sah:Alnylam Pharmaceuticals, Inc.: Employment. Fitzgerald:Alnylam Pharmaceuticals: Employment. Kotelianski:Alnylam Pharmaceuticals: Employment. Kaelin:Fibrogen: Consultancy, Equity Ownership.
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Wang, Jingya, Andrew G. Muntean, and Jay L. Hess. "ECSASB2 mediates MLL degradation during hematopoietic differentiation." Blood 119, no. 5 (2012): 1151–61. http://dx.doi.org/10.1182/blood-2011-06-362079.
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Abstract Mixed lineage leukemia (MLL) is a key epigenetic regulator of normal hematopoietic development and chromosomal translocations involving MLL are one of the most common genetic alterations in human leukemia. Here we show that ASB2, a component of the ECSASB E3 ubiquitin ligase complex, mediates MLL degradation through interaction with the PHD/Bromodomain region of MLL. Forced expression of ASB2 degrades MLL and reduces MLL transactivation activity. In contrast, the MLL-AF9 fusion protein does not interact with ASB2 and is resistant to ASB2 mediated degradation. Increased expression of ASB2 during hematopoietic differentiation is associated with decreased levels of MLL protein and down-regulation of MLL target genes. Knockdown of ASB2 leads to increased expression of HOXA9 and delayed cell differentiation. Our data support a model whereby ASB2 contributes to hematopoietic differentiation, in part, through MLL degradation and HOX gene down-regulation. Moreover, deletion of the PHD/Bromo region renders MLL fusion proteins resistant to ASB2-mediated degradation and may contribute to leukemogenesis.
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Yang, Qing, Jianwen Zhang, Shilei Xu та ін. "Knockdown of PHF5A Inhibits Migration and Invasion of HCC Cells via Downregulating NF-κB Signaling". BioMed Research International 2019 (15 січня 2019): 1–9. http://dx.doi.org/10.1155/2019/1621854.
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Background. Inflammation is the major risk factor for the progression of hepatocellular carcinoma (HCC), and the nuclear factor-κB (NF-κB) signaling plays the central role in the inflammation process. However, the activated mechanism of NF-κB signaling in HCC is unclear. Methods. The expression of PHF5A is examined by qPCR, western blotting, and immunohistochemistry (IHC) assay. The potential of PHF5A (PHD-finger domain protein 5a) for migration and invasion is examined by wound healing and Transwell assay. Luciferase reporter assay, western blotting, and qPCR were applied to explore the mechanism by which PHF5A is involved in progression of HCC. Results. PHF5A was significantly upregulated in HCC tissues and cells. Downregulation of PHF5A inhibits the migration and invasion of HCC cells. Further study demonstrated that PHF5A is implicated in HCC progression through NF-κB signaling. In addition, blocking the NF-κB signaling can weaken the stimulatory effect of PHF5A on migration and invasion of HCC cells. Conclusion. PHF5A expression is upregulated in HCC tissues, and depletion of PHF5A inhibits the migration and invasion of HCC cells. Further experiments demonstrated that PHF5A is implicated in NF-κB signaling and knockdown of PHF5A downregulates the activity of NF-κB pathway to inhibit the tumor progression. The above results provide the evidence that PHF5A plays an indispensable role in progressive effect of NF-κB pathway in HCC and may be a novel therapeutic target of HCC.
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Wang, Jingya, Andrew G. Muntean, and Jay L. Hess. "A Novel Ubiquitination Pathway Regulates MLL Activity During Hematopoietic Differentiation." Blood 116, no. 21 (2010): 743. http://dx.doi.org/10.1182/blood.v116.21.743.743.
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Abstract Abstract 743 MLL gene rearrangements are among the most common chromosomal abnormalities associated with both acute lymphoid (ALL) and myeloid (AML) leukemia. Both MLL and leukemogenic MLL fusion proteins directly regulate expression of HoxA9 and the co-factor Meis1. Normally Hoxa9 and Meis1 are expressed at high levels in early hematopoietic progenitors, where they promote HSC self-renewal. MLL fusion proteins block this physiologic down regulation so that Hoxa9 and Meis1 are persistently expressed, resulting in leukemia. The mechanisms through which the activity of MLL is normally regulated are poorly understood. MLL fusion proteins include the first 1400 amino acids of MLL and invariably delete the plant homeodomain (PHD)/Bromodomain regions (including 4 PHD fingers, with bromodomain between the 3rd and 4th PHD finger) and C terminal SET domain. Previously we showed that inclusion of the MLL PHD domain in MLL fusion proteins prevents transformation. To further explore the function of this potential regulatory domain, we identified proteins that interact with the CxxC and PHD domains by immunoaffinity purification and mass spectroscopy. These studies identified subunits of the Elongin-Cullin-Socs box (ECS) complex including Elongin B, Elongin C, Cullin 5 and Ankyrin Repeat and SOCS box (ASB) E3 ligases. Biochemical experiments on a panel of ASB proteins revealed that ASB2, which functions as a substrate recognition subunit of the ECS complex specifically and potently degrades MLL. Over expression of ASB2 enhanced the degradation of MLL, while ASB2 knockdown results in MLL protein stabilization. Moreover, co-expressed ASB2 abolished MLL mediated transcriptional activation of a HoxA9 reporter. The interaction region on ASB2 maps to the five N terminal ankyrin repeats. Since the ASB2 interaction is mediated through a region of MLL invariably deleted from fusion proteins, we predicted that MLL fusions would be significantly more stable than full length MLL. Indeed, we measured the half-life of wild type MLL to be ~7hrs, and ~16hrs in the presence of MG132 proteasome inhibition. In contrast, MLL-AF9 displayed a half-life of ~60hrs, and MG132 treatment slightly increased the half-life to ~76hrs. Gene expression analysis of different hematopoietic cell populations indicates that Asb2 expression increases dramatically with differentiation. Also, All-trans retinoid acid (ATRA) induced differentiation of NB4 and K562 cells is associated with up regulation of Asb2 and decreased MLL protein level and Hox gene expression, while MLL transcription is largely unchanged. Furthermore, expression of ASB2 in primary mouse bone marrow cells results in accelerated differentiation and decreased expression of several MLL target genes compared to vector control and over expression of ASB2 in MLL-fusion transformed murine cell lines dramatically decreased colony formation, consistent with recently published data that wild type MLL is required for MLL fusion transformation. Together this work reveals a novel ubiquitination pathway that regulates MLL at the posttranslational level, which is likely to be important for both normal hematopoiesis and the dysregulated transcription that is seen in leukemias with MLL rearrangements. Disclosures: No relevant conflicts of interest to declare.
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Marjoram, Lindsay, Ashley Alvers, M. Elizabeth Deerhake, et al. "Epigenetic control of intestinal barrier function and inflammation in zebrafish." Proceedings of the National Academy of Sciences 112, no. 9 (2015): 2770–75. http://dx.doi.org/10.1073/pnas.1424089112.
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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.
Dissertations / Theses on the topic "PHD Knockdown"
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Edwards, Catriona Helen. "Drug target identification in the cat flea by transcriptomics and gene knockdown." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=236461.
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Ctenocephalides felis is a major pest of companion animals worldwide. This project aimed to generate novel genetic resources for C. felis and develop tools to aid drug-target identification and validation. Sample handling methods were assessed and candidate reference genes validated, to ensure quality of RNA samples and reliable gene expression normalisation. Piercing C. felis samples prior to storage in RNAlater ensured RNA integrity was maintained over time. Glyceraldehyde 3-phosphate dehydrogenase , 60S ribosomal protein L19 and elongation factor-1α were demonstrated as stable reference genes across all comparisons tested. A C. felis transcriptome encompassing multiple developmental stages, sexes and tissues was sequenced and de novo assemblies produced with two assemblers, Trinity and Oases. Each assembly contained >100000 contigs. Annotation of the assemblies generated functional insight, such as top BLAST hits, GO annotations and signal peptide predictions. The Trinity assembly was deemed the highest quality and searched for genes of interest, involved in development. Expression analysis of selected transcripts across stadia gave insight into developmental processes, and demonstrated the utility of the transcriptome. This study was the first to demonstrate that C. felis can mount an RNAi response upon exposure to dsRNA. Knockdown of glutathione S-transferase σ (GSTσ), was demonstrated in adult C. felis: ≈80 % knockdown following microinjection of dsGSTσ; ≈64 % knockdown after soaking in dsGSTσ; ≈96 % knockdown after continuous feeding on dsGSTσ. RNAi machinery was identified in C. felis. siRNAi pathway components, Dicer 2 and Argonaute 2, were upregulated following dsRNA exposure. Dicer 2 was knocked-down by soaking in dsDicer2, although results of an “RNAi of RNAi” experiment were inconclusive. Transcripts encoding machinery putatively involved in dsRNA uptake and breakdown were also identified. Through these studies, this project has generated novel insights into C. felis biology and opened up new avenues for research.
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Le-Huu, Sinja Kim-Anh Verfasser], Dörthe [Akademischer Betreuer] Katschinski, Jürgen [Akademischer Betreuer] [Wienands, and Martin [Akademischer Betreuer] Oppermann. "Etablierung und Charakterisierung einer Tetracyclin-induzierbaren PHD2-Knockdown-HeLa-Zelllinie / Sinja Kim-Anh Le-Huu. Gutachter: Jürgen Wienands ; Martin Oppermann. Betreuer: Dörthe Katschinski." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2010. http://d-nb.info/1042671532/34.
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Melville, Heather. "Spatiotemporal analysis of apoptosis patterns in the developing brain of the Brd2-knockdown zebrafish embryo." Click here for download, 2009. http://proquest.umi.com/pqdweb?did=1851609811&sid=1&Fmt=2&clientId=3260&RQT=309&VName=PQD.
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Murphy, Tami J. "Phenotypic analysis of transcriptional co-activator, brd2, gene knockdowns in zebrafish (Danio rerio) embryos." Click here for download, 2007. http://proquest.umi.com/pqdweb?did=1288659571&sid=1&Fmt=2&clientId=3260&RQT=309&VName=PQD.
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Le-Huu, Sinja Kim-Anh. "Etablierung und Charakterisierung einer Tetracyclin-induzierbaren PHD2-Knockdown-HeLa-Zelllinie." Doctoral thesis, 2009. http://hdl.handle.net/11858/00-1735-0000-0006-AFA9-6.
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