Artykuły w czasopismach: „P53-regulated genes”

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Keegan, Lunec i Neal. "p53 and p53-regulated genes in bladder cancer". BJU International 82, nr 5 (listopad 1998): 710–20. http://dx.doi.org/10.1046/j.1464-410x.1998.00822.x.

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Xu, H., i M. R. El-Gewely. "P53 network — its downstream regulated genes". Biochemical Society Transactions 28, nr 5 (1.10.2000): A227. http://dx.doi.org/10.1042/bst028a227a.

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Klingler, H. Christoph. "p53 and p53 regulated genes in bladder cancer [review]". Current Opinion in Urology 9, nr 2 (marzec 1999): 172. http://dx.doi.org/10.1097/00042307-199903000-00015.

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Riley, Todd, Eduardo Sontag, Patricia Chen i Arnold Levine. "Transcriptional control of human p53-regulated genes". Nature Reviews Molecular Cell Biology 9, nr 5 (maj 2008): 402–12. http://dx.doi.org/10.1038/nrm2395.

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Yu, J., L. Zhang, P. M. Hwang, C. Rago, K. W. Kinzler i B. Vogelstein. "Identification and classification of p53-regulated genes". Proceedings of the National Academy of Sciences 96, nr 25 (7.12.1999): 14517–22. http://dx.doi.org/10.1073/pnas.96.25.14517.

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Lotem, J., H. Gal, R. Kama, N. Amariglio, G. Rechavi, E. Domany, L. Sachs i D. Givol. "Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes". Proceedings of the National Academy of Sciences 100, nr 11 (12.05.2003): 6718–23. http://dx.doi.org/10.1073/pnas.1031695100.

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Fiordaliso, F., A. Leri, D. Cesselli, F. Limana, B. Safai, B. Nadal-Ginard, P. Anversa i J. Kajstura. "Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death". Diabetes 50, nr 10 (1.10.2001): 2363–75. http://dx.doi.org/10.2337/diabetes.50.10.2363.

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Wang, Chao, Cui Rong Teo i Kanaga Sabapathy. "p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?" International Journal of Molecular Sciences 21, nr 4 (17.02.2020): 1346. http://dx.doi.org/10.3390/ijms21041346.

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Identification of p73 as a structural homolog of p53 fueled early studies aimed at determining if it was capable of performing p53-like functions. This led to a conundrum as p73 was discovered to be hardly mutated in cancers, and yet, TAp73, the full-length form, was found capable of performing p53-like functions, including transactivation of many p53 target genes in cancer cell lines. Generation of mice lacking p73/TAp73 revealed a plethora of developmental defects, with very limited spontaneous tumors arising only at a later stage. Concurrently, novel TAp73 target genes involved in cellular growth promotion that are not regulated by p53 were identified, mooting the possibility that TAp73 may have diametrically opposite functions to p53 in tumorigenesis. We have therefore comprehensively evaluated the TAp73 target genes identified and validated in human cancer cell lines, to examine their contextual relevance. Data from focused studies aimed at appraising if p53 targets are also regulated by TAp73—often by TAp73 overexpression in cell lines with non-functional p53—were affirmative. However, genome-wide and phenotype-based studies led to the identification of TAp73-regulated genes involved in cellular survival and thus, tumor promotion. Our analyses therefore suggest that TAp73 may not necessarily be p53’s natural substitute in enforcing tumor suppression. It has likely evolved to perform unique functions in regulating developmental processes and promoting cellular growth through entirely different sets of target genes that are not common to, and cannot be substituted by p53. The p53-related targets initially reported to be regulated by TAp73 may therefore represent an experimental possibility rather than the reality.

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Zhao, Renbin, Kurt Gish, Maureen Murphy, Yuxin Yin, Daniel Notterman, William H. Hoffman, Edward Tom, David H. Mack i Arnold J. Levine. "Analysis of p53-regulated gene expression patterns using oligonucleotide arrays". Genes & Development 14, nr 8 (15.04.2000): 981–93. http://dx.doi.org/10.1101/gad.14.8.981.

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Oligonucleotide microarrays were employed to quantitate mRNA levels from a large number of genes regulated by the p53 transcription factor. Responses to DNA damage and to zinc-inducible p53 were compared for their transcription patterns in cell culture. A cluster analysis of these data demonstrates that genes induced by γ radiation, UV radiation, and the zinc-induced p53 form distinct sets and subsets with a few genes in common to all these treatments. Cell type- or cell line-specific p53 responses were detected. When p53 proteins were induced with zinc, the kinetics of induction or repression of mRNAs from p53-responsive genes fell into eight distinct classes, five different kinetics of induction, and three different kinetics of repression. In addition, low levels of p53 in a cell induced or repressed only a subset of genes observed at higher p53 levels. The results of this study demonstrate that the nature of the p53 response in diverse mRNA species depends on the levels of p53 protein in a cell, the type of inducing agent or event, and the cell type employed. Of 6000 genes examined for p53 regulatory responses, 107 induced and 54 repressed genes fell into categories of apoptosis and growth arrest, cytoskeletal functions, growth factors and their inhibitors, extracellular matrix, and adhesion genes.

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Łasut-Szyszka, Barbara, Beata Małachowska, Agnieszka Gdowicz-Kłosok, Małgorzata Krześniak, Magdalena Głowala-Kosińska, Artur Zajkowicz i Marek Rusin. "Transcriptome Analysis of Cells Exposed to Actinomycin D and Nutlin-3a Reveals New Candidate p53-Target Genes and Indicates That CHIR-98014 Is an Important Inhibitor of p53 Activity". International Journal of Molecular Sciences 22, nr 20 (14.10.2021): 11072. http://dx.doi.org/10.3390/ijms222011072.

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Co-treatment with actinomycin D and nutlin-3a (A + N) strongly activates p53. Previously we reported that CHIR-98014 (GSK-3 kinase inhibitor), acting in cells exposed to A + N, prevents activation of TREM2-an innate immunity and p53-regulated gene associated with Alzheimer’s disease. In order to find novel candidate p53-target genes and genes regulated by CHIR-98014, we performed RNA-Seq of control A549 cells and the cells exposed to A + N, A + N with CHIR-98014 or to CHIR-98014. We validated the data for selected genes using RT-PCR and/or Western blotting. Using CRISPR/Cas9 technology we generated p53-deficient cells. These tools enabled us to identify dozens of candidate p53-regulated genes. We confirmed that p53 participates in upregulation of BLNK, APOE and IRF1. BLNK assists in activation of immune cells, APOE codes for apolipoprotein associated with Alzheimer’s disease and IRF1 is activated by interferon gamma and regulates expression of antiviral genes. CHIR-98014 prevented or inhibited the upregulation of a fraction of genes stimulated by A + N. Downregulation of GSK-3 did not mimic the activity of CHIR-98014. Our data generate the hypothesis, that an unidentified kinase inhibited by CHIR-98014, participates in modification of p53 and enables it to activate a subset of its target genes, e.g., the ones associated with innate immunity.

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Dal-Bo, Michele, Paola Secchiero, Massimo Degan, Riccardo Bomben, Dania Benedetti, Antonella Zucchetto, Daniela Marconi i in. "B-Cell Chronic Lymphocytic Leukemia Cells Exposed to the Non-Genotoxic p53 Activator Nutlin-3 Are Characterized by a Specific Gene Expression Signature." Blood 114, nr 22 (20.11.2009): 4374. http://dx.doi.org/10.1182/blood.v114.22.4374.4374.

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Abstract Abstract 4374 Introduction p53 plays a key role in determining the clinical features of B cell chronic lymphocytic leukemia (CLL). Disruption of p53 by point mutations, deletion at 17p13, or both, occurs in a fraction of cases at diagnosis and predicts poor survival and chemorefractoriness. In cells with functional p53, p53 activity is inhibited through interaction with MDM2. In fact, p53 can be activated upon exposure of cells to inhibitors of p53/MDM2 interaction, like Nutlins. Exposure of CLL cells to Nutlin-3 is effective in raising the levels of p53 protein with subsequent induction of cell cycle arrest and/or apoptosis, independently of the most relevant prognostic markers. The aim of the present study was to analyze the gene expression profile (GEP) induced by Nutlin-3 exposure in primary CLL cells from p53wt and p53del/mut cases. Patients and methods purified cells from 24 PB CLL samples, all characterized for IGHV mutational status, CD38 and ZAP-70 and p53 mutations (16 p53wt CLL, 8 p53del/mut CLL of which 6 with del17p13 and p53 mutations, 1 with del17p13 alone, and 1 with p53 mutations alone), were exposed to 10 mM Nutlin-3 for 24 hours. GEP was performed using a dual labelling strategy; the differential expression of the below reported genes were validated by quantitative real-time PCR. Results i) signature of Nutlin-3 exposure in p53wt CLL: 144 differentially expressed genes (143 up-regulated, 1 down-regulated) were correlated with response to Nutlin-3. Among the over-expressed genes, several genes were related to apoptosis (e.g. BAX, BBC3, E124, IKIP, FAS, LRDD, FLJ11259, TRIAP1, GADD45, TP53INP1, ISG20L1, ZMAT3, TNFRS10C, TNFRSF10B/TRAIL-R2), while other genes (e.g. MDM2, CDKN1A, PCNA) were up-regulated by Nutlin-3 as a part of a negative feed-back mechanism. Of note, this signature was not shared by 3/16 p53wt cases (identified as “non-responder” p53wt CLL) and 7/8 p53del/mut cases (identified as “non-responder” p53del/mut CLL); consistently, cells from these cases were also significantly resistant to the in-vitro cytotoxic effects of Nutlin-3; ii) signature of Nutlin-3 “non-responder” p53wt CLL: by comparing the constitutive GEP of 13 “responder” versus 3 “non-responder” p53wt CLL, we obtained 278 differentially expressed genes, 149 up-regulated and 129 down-regulated in “non-responder” p53wt CLL. Among up-regulated genes, we focused on MDM4/MDMX, a gene whose product was known to have an inhibitor activity of p53-dependent transcription and to form Nutlin-3 resistant complexes with p53. Among down-regulated genes, validations were made for BIRC4BP, whose product is known to act as an antagonist of the anti-apoptotic protein XIAP; iii) signature of Nutlin-3 “non-responder” p53del/mut CLL: by comparing the constitutive GEP of 13 “responder” versus 7 “non-responder” p53del/mut cases, we obtained 72 differentially expressed genes, 26 up-regulated and 46 down-regulated (31/46 located at the 17p segment) in “non-responder” p53del/mut CLL. Validations were made for several genes whose products display pro-apoptotic activities (e.g. PSMB6, RPL26 and ZBTB4, located at 17p segment, and GNAZ located at chromosome 22) among down-regulated genes, and ARHGDIA, whose gene product displays anti-apoptotic activities and mediates cellular resistance to chemotherapeutic agents, among up-regulated genes. Notably, CLL cells (n=43) displayed constitutively higher levels of MDM4/MDMX (p<0.0001) and ARHGDIA (p=0.0002) transcripts than purified normal B cells (n=15), irrespectively to the major biologic prognosticators. Conclusions specific gene-sets and GEP were documented to be associated with response or resistance to Nutlin-3 exposure in p53wt or p53del/mut CLL. These findings may help to identify novel molecular targets for CLL therapy. Disclosures: No relevant conflicts of interest to declare.

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Li, Yuwen, Jiao Liu, Nathan McLaughlin, Dimcho Bachvarov, Zubaida Saifudeen i Samir S. El-Dahr. "Genome-wide analysis of the p53 gene regulatory network in the developing mouse kidney". Physiological Genomics 45, nr 20 (15.10.2013): 948–64. http://dx.doi.org/10.1152/physiolgenomics.00113.2013.

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Despite mounting evidence that p53 senses and responds to physiological cues in vivo, existing knowledge regarding p53 function and target genes is largely derived from studies in cancer or stressed cells. Herein we utilize p53 transcriptome and ChIP-Seq (chromatin immunoprecipitation-high throughput sequencing) analyses to identify p53 regulated pathways in the embryonic kidney, an organ that develops via mesenchymal-epithelial interactions. This integrated approach allowed identification of novel genes that are possible direct p53 targets during kidney development. We find the p53-regulated transcriptome in the embryonic kidney is largely composed of genes regulating developmental, morphogenesis, and metabolic pathways. Surprisingly, genes in cell cycle and apoptosis pathways account for <5% of differentially expressed transcripts. Of 7,893 p53-occupied genomic regions (peaks), the vast majority contain consensus p53 binding sites. Interestingly, 78% of p53 peaks in the developing kidney lie within proximal promoters of annotated genes compared with 7% in a representative cancer cell line; 25% of the differentially expressed p53-bound genes are present in nephron progenitors and nascent nephrons, including key transcriptional regulators, components of Fgf, Wnt, Bmp, and Notch pathways, and ciliogenesis genes. The results indicate widespread p53 binding to the genome in vivo and context-dependent differences in the p53 regulon between cancer, stress, and development. To our knowledge, this is the first comprehensive analysis of the p53 transcriptome and cistrome in a developing mammalian organ, substantiating the role of p53 as a bona fide developmental regulator. We conclude p53 targets transcriptional networks regulating nephrogenesis and cellular metabolism during kidney development.

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Kim, Jung-Sik, Carolyn Lee, Challice L. Bonifant, Habtom Ressom i Todd Waldman. "Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA". Molecular and Cellular Biology 27, nr 2 (23.10.2006): 662–77. http://dx.doi.org/10.1128/mcb.00537-06.

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ABSTRACT In an effort to identify genes whose expression is regulated by activated phosphatidylinositol 3-kinase (PI3K) signaling, we performed microarray analysis and subsequent quantitative reverse transcription-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN−/− cells via an Akt1-dependent and p14ARF-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescence-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic, but not wild-type, PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on phosphatidylinositol (3, 4, 5)-triphosphate-induced mitogenesis during human cancer pathogenesis.

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Kadioglu, Onat, Mohamed Saeed, Nuha Mahmoud, Shaymaa Azawi, Kristin Mrasek, Thomas Liehr i Thomas Efferth. "Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion". Archives of Toxicology 95, nr 3 (30.01.2021): 959–74. http://dx.doi.org/10.1007/s00204-021-02979-4.

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AbstractTP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 −/−) with TP53 deletion, a sub-line derived from HCT116-p53 +/+ cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53 −/− cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53 −/− cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53 +/+ cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.

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Zhang, Cong, Jiangfei Zhou, Shengnan Li, Kairui Cai, Xiangling Guo, Chengshui Liao i Chen Wang. "Bursal Hexapeptide, A Potential Immunomodulator, Inhibits Tumor Cells Proliferation via p53 Signaling Pathway". Anti-Cancer Agents in Medicinal Chemistry 18, nr 11 (28.01.2019): 1582–88. http://dx.doi.org/10.2174/1871520618666180604094618.

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Background: The Bursa of Fabricius (BF) is acknowledged as the central humoral immune organ unique to birds. Bursal Hexapeptide (BHP, AGCCNG) is a recently reported bursal-derived bioactive peptide. However, there are few reports of the molecular basis of the mechanism on immune induction and potential antitumor activity of BHP. Method: In this paper, Gene microarray analyses demonstrated that BHP regulated expression of 1347 genes, of which 832 were up-regulated and 515 were down-regulated. Differentially expressed genes involved in various pathways were identified, of which 16 pathways were associated with immune responses and tumorigenic processes. Result: Specifically, we found that BHP selectively inhibited tumor cell proliferation. Furthermore, BHP enhanced antitumor factor p53 luciferase activity and stimulated expression of p53, p21, and p130 protein. Moreover, we observed that the inhibitory effect of BHP on cell proliferation and premature senescence in a p53-dependent manner. Conclusion: Taken together, we uncovered that BHP may be involved in antitumor suppressor via p53 signaling pathway.

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Gong, Lili, Fangyuan Liu, Zhen Xiong, Ruili Qi, Zhongwen Luo, Xiaodong Gong, Qian Nie i in. "Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes". Proceedings of the National Academy of Sciences 115, nr 17 (5.04.2018): E3987—E3995. http://dx.doi.org/10.1073/pnas.1715237115.

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Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53–heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD.

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Miyajima, Chiharu, Yuki Kawarada, Yasumichi Inoue, Chiaki Suzuki, Kana Mitamura, Daisuke Morishita, Nobumichi Ohoka, Takeshi Imamura i Hidetoshi Hayashi. "Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence". Cells 9, nr 1 (9.01.2020): 171. http://dx.doi.org/10.3390/cells9010171.

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Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.

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Zhang, Ying, Collin Dube, Myron Gibert, Nichola Cruickshanks, Baomin Wang, Maeve Coughlan, Yanzhi Yang i in. "The p53 Pathway in Glioblastoma". Cancers 10, nr 9 (1.09.2018): 297. http://dx.doi.org/10.3390/cancers10090297.

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The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment. TP53 is one of the most commonly deregulated genes in cancer. The p53-ARF-MDM2 pathway is deregulated in 84% of glioblastoma (GBM) patients and 94% of GBM cell lines. Deregulated p53 pathway components have been implicated in GBM cell invasion, migration, proliferation, evasion of apoptosis, and cancer cell stemness. These pathway components are also regulated by various microRNAs and long non-coding RNAs. TP53 mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein. These relatively understudied GOF p53 mutants promote GBM malignancy, possibly by acting as transcription factors on a set of genes other than those regulated by wild type p53. Their expression correlates with worse prognosis, highlighting their potential importance as markers and targets for GBM therapy. Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies.

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Friedlander, P., Y. Haupt, C. Prives i M. Oren. "A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis." Molecular and Cellular Biology 16, nr 9 (wrzesień 1996): 4961–71. http://dx.doi.org/10.1128/mcb.16.9.4961.

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Human wild-type (wt) p53 can induce apoptosis in transiently transfected H1299 cells maintained at 37 degrees C, whereas tumor-derived mutant forms of p53 (with the mutation Ala-143, His-175, or Trp-248) fail to do so. At 37 degrees C, p53 with a mutation to Ala at amino acid 143 (p53Ala143) was transcriptionally inactive. However, at 32 degrees C, p53Ala143 strongly activated transcription from several physiologically relevant p53-responsive promoters, to extents similar or greater than that of wt p53. Unexpectedly, p53Ala143 was defective in inducing apoptosis in H1299 cells at 32 degrees C. Concomitantly with the loss of apoptotic activity, p53Ala143 was found to be deficient in its ability to activate transcription from the p53-responsive portions of the Bax and insulin-like growth factor-binding protein 3 gene promoters. It is proposed that there may exist distinct classes of p53-responsive promoters, whose ability to be activated by p53 can be regulated differentially. Such differential regulation may have functional consequences for the effects of p53 on cell fate.

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Nigro, J. M., R. Sikorski, S. I. Reed i B. Vogelstein. "Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae". Molecular and Cellular Biology 12, nr 3 (marzec 1992): 1357–65. http://dx.doi.org/10.1128/mcb.12.3.1357-1365.1992.

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Human wild-type and mutant p53 genes were expressed under the control of a galactose-inducible promoter in Saccharomyces cerevisiae. The growth rate of the yeast was reduced in cells expressing wild-type p53, whereas cells transformed with mutant p53 genes derived from human tumors were less affected. Coexpression of the normal p53 protein with the human cell cycle-regulated protein kinase CDC2Hs resulted in much more pronounced growth inhibition that for p53 alone. Cells expressing p53 and CDC2Hs were partially arrested in G1, as determined by morphological analysis and flow cytometry. p53 was phosphorylated when expressed in the yeast, but differences in phosphorylation did not explain the growth inhibition attributable to coexpression of p53 and CDC2Hs. These results suggest that wild-type p53 has a growth-inhibitory activity in S. cerevisiae similar to that observed in mammalian cells and suggests that this yeast may provide a useful model for defining the pathways through which p53 acts.

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Nigro, J. M., R. Sikorski, S. I. Reed i B. Vogelstein. "Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae." Molecular and Cellular Biology 12, nr 3 (marzec 1992): 1357–65. http://dx.doi.org/10.1128/mcb.12.3.1357.

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Human wild-type and mutant p53 genes were expressed under the control of a galactose-inducible promoter in Saccharomyces cerevisiae. The growth rate of the yeast was reduced in cells expressing wild-type p53, whereas cells transformed with mutant p53 genes derived from human tumors were less affected. Coexpression of the normal p53 protein with the human cell cycle-regulated protein kinase CDC2Hs resulted in much more pronounced growth inhibition that for p53 alone. Cells expressing p53 and CDC2Hs were partially arrested in G1, as determined by morphological analysis and flow cytometry. p53 was phosphorylated when expressed in the yeast, but differences in phosphorylation did not explain the growth inhibition attributable to coexpression of p53 and CDC2Hs. These results suggest that wild-type p53 has a growth-inhibitory activity in S. cerevisiae similar to that observed in mammalian cells and suggests that this yeast may provide a useful model for defining the pathways through which p53 acts.

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Lou, Guohua, Yanning Liu, Shanshan Wu, Jihua Xue, Fan Yang, Haijing Fu, Min Zheng i Zhi Chen. "The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis". Cellular Physiology and Biochemistry 35, nr 6 (2015): 2192–202. http://dx.doi.org/10.1159/000374024.

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Background: The anti-tumor effects of quercetin have been reported, but the underlying molecular mechanisms remain to be elucidated. The aim of present study was to explore the role of miRNA in the anticancer effects of quercetin. Methods: The differential miRNAs expression between the HepG2 and Huh7 cells treated by quercetin were detected by microarray. The xCELLigence, Flow cytometry, RT-PCR and Western blot were used to analyze the cell proliferation, cell apoptosis, cell cycle arrest, anti-tumor genes, and protein expression. Results: miR-34a was up-regulated in HepG2 cells treated by quercetin exhibiting wild-type p53. When inhibiting the miR-34a, the sensitivity of the cells to quercetin decreased and the expression of the SIRT1 was up-regulated, but the acetylation of p53 and the expression of some genes related to p53 down-regulated. Conclusion: miR-34a plays an important role in the anti-tumor effects of querctin in HCC, miR-34a may be a tiemolecule between the p53 and SIRT1 and is composed of a p53/miR-34a/SIRT1 signal feedback loop, which could enhance apoptosis signal and significantly promote cell apoptosis.

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Kukita, Asako, Kenbun Sone, Syuzo Kaneko, Eiryo Kawakami, Shinya Oki, Machiko Kojima, Miku Wada i in. "The Histone Methyltransferase SETD8 Regulates the Expression of Tumor Suppressor Genes via H4K20 Methylation and the p53 Signaling Pathway in Endometrial Cancer Cells". Cancers 14, nr 21 (31.10.2022): 5367. http://dx.doi.org/10.3390/cancers14215367.

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The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

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Boehme, S. A., i M. J. Lenardo. "TCR-mediated death of mature T lymphocytes occurs in the absence of p53." Journal of Immunology 156, nr 11 (1.06.1996): 4075–78. http://dx.doi.org/10.4049/jimmunol.156.11.4075.

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Abstract The p53 protein plays an important role in various forms of thymocyte apoptosis, however its role in mature T lymphocyte death caused by TCR stimulation has not been examined. We demonstrate here that T cell blasts derived from mice containing a germ-line deficiency of the p53 tumor suppressor gene are susceptible to TCR-induced apoptosis to the same degree as wild-type T cells. TCR stimulation of both resting and proliferatingT cells results in up-regulated expression of the p53-induced genes Bax and p21, and the induction of these genes appears reduced in T cells that are deficient in p53. Thus, while activation of p53-dependent genes following TCR stimulation is defective in p53-/- T cells, there is no impairment in their ability to undergo apoptosis. These results suggest that TCR-mediated apoptosis of mature T cells takes place via a pathway that is independent of p53.

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Hannemann, Holger, Kyle Rosenke, John M. O'Dowd i Elizabeth A. Fortunato. "The Presence of p53 Influences the Expression of Multiple Human Cytomegalovirus Genes at Early Times Postinfection". Journal of Virology 83, nr 9 (18.02.2009): 4316–25. http://dx.doi.org/10.1128/jvi.02075-08.

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ABSTRACT Human cytomegalovirus (HCMV) is a common cause of morbidity and mortality in immunocompromised and immunosuppressed individuals. During infection, HCMV is known to employ host transcription factors to facilitate viral gene expression. To further understand the previously observed delay in viral replication and protein expression in p53 knockout cells, we conducted microarray analyses of p53+/+ and p53−/− immortalized fibroblast cell lines. At a multiplicity of infection (MOI) of 1 at 24 h postinfection (p.i.), the expression of 22 viral genes was affected by the absence of p53. Eleven of these 22 genes (group 1) were examined by real-time reverse transcriptase, or quantitative, PCR (q-PCR). Additionally, five genes previously determined to have p53 bound to their nearest p53-responsive elements (group 2) and three control genes without p53 binding sites in their upstream sequences (group 3) were also examined. At an MOI of 1, >3-fold regulation was found for five group 1 genes. The expression of group 2 and 3 genes was not changed. At an MOI of 5, all genes from group 1 and four of five genes from group 2 were found to be regulated. The expression of control genes from group 3 remained unchanged. A q-PCR time course of four genes revealed that p53 influences viral gene expression most at immediate-early and early times p.i., suggesting a mechanism for the reduced and delayed production of virions in p53−/− cells.

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Hearnes, Jamie M., Deborah J. Mays, Kristy L. Schavolt, Luojia Tang, Xin Jiang i Jennifer A. Pietenpol. "Chromatin Immunoprecipitation-Based Screen To Identify Functional Genomic Binding Sites for Sequence-Specific Transactivators". Molecular and Cellular Biology 25, nr 22 (15.11.2005): 10148–58. http://dx.doi.org/10.1128/mcb.25.22.10148-10158.2005.

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ABSTRACT In various human diseases, altered gene expression patterns are often the result of deregulated gene-specific transcription factor activity. To further understand disease on a molecular basis, the comprehensive analysis of transcription factor signaling networks is required. We developed an experimental approach, combining chromatin immunoprecipitation (ChIP) with a yeast-based assay, to screen the genome for transcription factor binding sites that link to transcriptionally regulated target genes. We used the tumor suppressor p53 to demonstrate the effectiveness of the method. Using primary and immortalized, nontransformed cultures of human mammary epithelial cells, we isolated over 100 genomic DNA fragments that contain novel p53 binding sites. This approach led to the identification and validation of novel p53 target genes involved in diverse signaling pathways, including growth factor signaling, protein kinase/phosphatase signaling, and RNA binding. Our results yield a more complete understanding of p53-regulated signaling pathways, and this approach could be applied to any number of transcription factors to further elucidate complex transcriptional networks.

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Qiao, X., H. Wang, X. Wang, B. Zhao i J. Liu. "Microarray technology reveals potentially novel genes and pathways involved in non-functioning pituitary adenomas". Balkan Journal of Medical Genetics 19, nr 2 (31.12.2016): 5–16. http://dx.doi.org/10.1515/bjmg-2016-0030.

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AbstractMicroarray data of non-functioning pituitary adenomas (NFPAs) were analyzed to disclose novel genes and pathways involved in NFPA tumorigenesis. Raw microarray data were downloaded from Gene Expression Omnibus. Data pre-treatment and differential analysis were conducted using packages in R. Functional and pathway enrichment analyses were performed using package GOs-tats. A protein-protein interaction (PPI) network was constructed using server STRING and Cytoscape. Known genes involved in pituitary adenomas (PAs), were obtained from the Comparative Toxicogenomics Database. A total of 604 differentially expressed genes (DEGs) were identifed between NFPAs and controls, including 177 up- and 427 down-regulated genes. Jak-STAT and p53 signaling pathways were significantly enriched by DEGs. The PPI network of DEGs was constructed, containing 99 up- and 288 down-regulated known disease genes (e.g. EGFR and ESR1) as well as 16 up- and 17 down-regulated potential novel NFPAs-related genes (e.g. COL4A5, LHX3, MSN, and GHSR). Genes like COL4A5, LHX3, MSN, and GHSR and pathways such as p53 signaling and Jak-STAT signaling, might participate in NFPA development. Although further validations are required, these findings might provide guidance for future basic and therapy researches.

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Wu, Chiao-En, Chen-Yang Huang, Chiao-Ping Chen, Yi-Ru Pan, John Wen-Cheng Chang, Jen-Shi Chen, Chun-Nan Yeh i John Lunec. "WIP1 Inhibition by GSK2830371 Potentiates HDM201 through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells". Cancers 13, nr 15 (31.07.2021): 3876. http://dx.doi.org/10.3390/cancers13153876.

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Background: Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct. It is the second most common primary liver cancer and has a poor prognosis. Activation of p53 by targeting its negative regulators, MDM2 and WIP1, is a potential therapy for wild-type p53 cancers, but few reports for iCCA or liver adenocarcinoma exist. Methods: Both RBE and SK-Hep-1 liver adenocarcinoma cell lines were treated with the HDM201 (Siremadlin) MDM2-p53 binding antagonist alone or in combination with the GSK2830371 WIP1 phosphatase inhibitor. Cell proliferation, clonogenicity, protein and mRNA expression, cell cycle distribution, and RNA sequencing were performed to investigate the effect and mechanism of this combination. Results: GSK2830371 alone demonstrated minimal activity on proliferation and colony formation, but potentiated growth inhibition (two-fold decrease in GI50) and cytotoxicity (four-fold decrease in IC50) by HDM201 on RBE and SK-Hep-1 cells. HDM201 increased p53 protein expression, leading to transactivation of downstream targets (p21 and MDM2). Combination with GSK2830371 increased p53 phosphorylation, resulting in an increase in both p53 accumulation and p53-dependent trans-activation. G2/M arrest was observed by flow cytometry after this treatment combination. RNA sequencing identified 21 significantly up-regulated genes and five downregulated genes following p53 reactivation by HDM201 in combination with GSK2830371 at 6 h and 24 h time points compared with untreated controls. These genes were predominantly known transcriptional targets regulated by the p53 signaling pathway, indicating enhanced p53 activation as the predominant effect of this combination. Conclusion: The current study demonstrated that GSK2830371 enhanced the p53-dependent antiproliferative and cytotoxic effect of HDM201 on RBE and SK-Hep-1 cells, providing a novel strategy for potentiating the efficacy of targeting the p53 pathway in iCCA.

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Ling, Xiaoyang, Ye Chen, Peter P. Ruvolo, Vivian Ruvolo, Zhiqiang Wang, Min Zhang, Yuexi Shi, Marina Konopleva, Richard E. Davis i Michael Andreeff. "Unique Effects of p53−/− Leukemic Cells On Mesenchymal Stromal Cell Gene Expression Profile in Vitro". Blood 120, nr 21 (16.11.2012): 3468. http://dx.doi.org/10.1182/blood.v120.21.3468.3468.

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Abstract Abstract 3468 Mesenchymal stromal cells (MSC) participate in the generation of the microenvironmental bone marrow niche which protects normal and leukemic stem cells from injuries, including chemotherapy. MSC produce numerous factors that aid in this function; however, little is known about how leukemic cells affect MSC. In this study, paired murine AML cells, MLL/ENL/FIT3-ITD/p53−/− and MLL/ENL/FIT3-ITD/p53wt, originally derived from C57BL/6 mice (Zuber et al. Genes & Dev. 2009), were co-cultured with MSC from the same strain. After 48 hrs, MSC were isolated by FACS sorting using CD45−/PDGFr+ as markers. Total RNA was profiled on Illumina WG6 mouse whole-genome bead arrays by standard procedures. The significance analysis of microarrays (SAM) method identified 429 differentially-expressed genes (DEG) whose expression in MSC differed significantly (false discovery rate, 10%) in co-cultures with p53−/− (C78) vs. p53wt (C147) leukemic cells. Differences in these DEG were highly consistent in replicates (Figure 1). The results demonstrate that: 1) p53 status (p53−/− vs. p53wt) of AML cells affects GEP patterns in co-cultured MSC. Comparison of the GEP in MSC co-cultured with p53−/− (78) or p53wt (147) (Fig 1) identified the following 5 genes that showed the most significant differences (up- or down-regulated): up-regulated: WNT16, WNT5, IGFBp5, GCNT1, ATP1B1; down-regulated: NOS2, DCN, CCL7, CCL2, CAR9, CCL4. These were selected for qPCR validation, and the results confirmed the array data. In addition, immunohistochemical staining showed that WNT16 was up-regulated in MSC co-cultured with p53wt leukemic cells. In addition, CXCL5 was found up-regulated in MSC co-cultured with p53−/− leukemic cells. These results were consistent with the GEP data. 2) Leukemic cells alter MSC Signaling proteins in vitro: Western blotting showed that Stat3, Akt, PTEN, CXCL5 and HIF-1α were up- regulated in MSC co-cultured with p53−/− leukemic cells as compared to p53wt leukemic cells (48 hrs). Additional analyses showed that the downstream targets of HIF-1α, VEGFa and VEGFc, but not VEGFb, were up-regulated. Taken together, these results suggest that 1) leukemic cells with different p53 genetic background co-cultured with normal MSC have profoundly differential effects on GEP of normal MSC; 2) MSC co-cultured with p53−/− leukemic cells resulted in increased levels of onco-proteins such as Akt and HIF-1α when compared to MSC co-cultured with p53wt leukemic cells. Results suggest, for the first time, that the genetics of leukemic cells determines gene expression in co-cultured MSC. In vivo experiments are in progress to provide in vivo evidence for the existence of a novel model of leukemia-stroma interactions where the genetics of the tumor cell impacts stromal cell biology. Disclosures: No relevant conflicts of interest to declare.

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Menendez, Daniel, Alberto Inga i Michael A. Resnick. "The Biological Impact of the Human Master Regulator p53 Can Be Altered by Mutations That Change the Spectrum and Expression of Its Target Genes". Molecular and Cellular Biology 26, nr 6 (15.03.2006): 2297–308. http://dx.doi.org/10.1128/mcb.26.6.2297-2308.2006.

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ABSTRACT Human tumor suppressor p53 is a sequence-specific master regulatory transcription factor that targets response elements (REs) in many genes. p53 missense mutations in the DNA-binding domain are often cancer associated. As shown with systems based on the yeast Saccharomyces cerevisiae, p53 mutants can alter the spectra and intensities of transactivation from individual REs. We address directly in human cells the relationship between changes in the p53 master regulatory network and biological outcomes. Expression of integrated, tightly regulated DNA-binding domain p53 mutants resulted in many patterns of apoptosis and survival following UV or ionizing radiation, or spontaneously. These patterns reflected changes in the spectra and activities of target genes, as demonstrated for P21, MDM2, BAX, and MSH2. Thus, as originally proposed for “master genes of diversity,” p53 mutations in human cells can differentially influence target gene transactivation, resulting in a variety of biological consequences which, in turn, might be expected to influence tumor development and therapeutic efficacy.

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Szak, Suzanne T., Deborah Mays i Jennifer A. Pietenpol. "Kinetics of p53 Binding to Promoter Sites In Vivo". Molecular and Cellular Biology 21, nr 10 (15.05.2001): 3375–86. http://dx.doi.org/10.1128/mcb.21.10.3375-3386.2001.

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ABSTRACT Downstream target genes of p53 are thought to mediate its tumor-suppressive activity, but it is unknown whether differential transactivation of these genes is regulated at the level of p53 binding to their promoters. To address this issue, p53 binding in vivo to consensus sites in the p21Waf1, MDM2, and PIG3 promoters was investigated in cells exposed to adriamycin (ADR) or ionizing radiation as well as in an inducible p53 cell line. p53-DNA complexes were cross-linked in vivo by treating the cells with formaldehyde and processed by chromatin immunoprecipitation-PCR. This methodology allowed for the analysis of relevant p53-DNA complexes by preventing redistribution of cellular components upon collection of cell extracts. Increased p53 binding to the p21Waf1, MDM2, and PIG3 promoters occurred within 2 h after p53 activation; however, significant increases in PIG3 transcription did not occur until 15 h after p53 binding. Gel shift analyses indicated that p53 had lower affinity for the consensus binding site in the PIG3 promoters compared to its consensus sites in the p21 and MDM2 genes, which suggests that additional factors may be required to stabilize the interaction of p53 with the PIG3 promoter. Further, acetylated p53 (Lys382) was found in chemically cross-linked complexes at all promoter sites examined after treatment of cells with ADR. In summary, the kinetics of p53 binding in vivo to target gene regulatory regions does not uniformly correlate with target gene mRNA expression for the p53 target genes examined. Our results suggest that target genes with low-affinity p53 binding sites may require additional events and will have delayed kinetics of induction compared to those with high-affinity binding sites.

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Tassabehji, Nadine M., Jacob W. Vanlandingham i Cathy W. Levenson. "Copper Alters the Conformation and Transcriptional Activity of the Tumor Suppressor Protein p53 in Human Hep G2 Cells". Experimental Biology and Medicine 230, nr 10 (listopad 2005): 699–708. http://dx.doi.org/10.1177/153537020523001002.

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The tumor suppressor protein p53 plays a role in the molecular response to DNA damage by acting as a DNA-binding transcription factor that regulates specific target genes to arrest the cell cycle, induce repair mechanisms, and initiate apoptotic cell death. To test the effect of copper on the transcriptional activity of p53, Hep G2 cells were transiently transfected with a luciferase reporter gene downstream from multiple p53 response elements. Co-transfection with the p53 gene resulted in a 6-fold increase in luciferase activity, showing that p53 acts as a transcription factor in this system. However, in the presence of copper, luciferase activity was significantly reduced. Oligonucleotide arrays representing 145 known p53-associated genes were hybridized with biotinylated cDNAs from mRNA extracted from control and copper-treated Hep G2 cells. Among the genes that were differentially regulated were fos, RB1, glutathione peroxidase, TGF-β, and 15-lipoxygenase, a gene known to be activated by mutant p53. Although control Hep G2 cells synthesize wild-type p53, immunocytochemistry identified not only wild type, but also mutant p53 in the presence of copper and other agents that induce oxidative damage. Thus, this report not only identifies genes that may play a role in copper-mediated apoptosis, but also suggests that copper-induced oxidative processes result in the synthesis of mutant p53 with altered transcriptional properties.

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Kannan, Karuppiah, Ninette Amariglio, Gideon Rechavi, Yasmin Yaakov, Naftali Kaminski, Gad Getz, Eitan Domany i David Givol. "Primary and secondary target genes regulated by p53 identified by DNA microarrays". Nature Genetics 27, S4 (kwiecień 2001): 63. http://dx.doi.org/10.1038/87146.

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Kannan, Karuppiah, Ninette Amariglio, Gideon Rechavi, Jasmine Jakob-Hirsch, Itai Kela, Naftali Kaminski, Gad Getz, Eytan Domany i David Givol. "DNA microarrays identification of primary and secondary target genes regulated by p53". Oncogene 20, nr 18 (kwiecień 2001): 2225–34. http://dx.doi.org/10.1038/sj.onc.1204319.

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Arizti, Paz, Li Fang, Iha Park, Yuxin Yin, Ellen Solomon, Toru Ouchi, Stuart A. Aaronson i Sam W. Lee. "Tumor Suppressor p53 Is Required To Modulate BRCA1 Expression". Molecular and Cellular Biology 20, nr 20 (15.10.2000): 7450–59. http://dx.doi.org/10.1128/mcb.20.20.7450-7459.2000.

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ABSTRACT Individuals carrying mutations in BRCA1 orp53 genes are predisposed to a variety of cancers, and both tumor suppressor genes have been implicated in DNA damage response pathways. We have analyzed a possible functional link betweenp53 and BRCA1 genes. Here we show that BRCA1 expression levels are down-regulated in response to p53 induction in cells that undergo either growth arrest, senescence, or apoptosis. Physiological stimuli, such as exposure to DNA-damaging agents, also result in negative regulation of BRCA1 levels in a p53-dependent manner prior to causing cell cycle arrest. Nuclear run-on experiments and luciferase reporter assays demonstrate that the changes in BRCA1 expression are mainly due to transcriptional repression induced by p53. In conclusion, the data show that BRCA1 expression levels are controlled by the presence and activity of wild-type p53 and suggest the existence of an intracellular p53/BRCA1 pathway in the response of cells to stress conditions.

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Kim, Bu-Yeo, Seo-Young Lee i Sun-Ku Chung. "Differential Transcriptional Regulation of Polymorphic p53 Codon 72 in Metabolic Pathways". International Journal of Molecular Sciences 22, nr 19 (6.10.2021): 10793. http://dx.doi.org/10.3390/ijms221910793.

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p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells. To investigate the functional differences of polymorphic p53 codon 72, we constructed isogenic lines encoding each polymorphic p53 codon 72 based on induced pluripotent stem cells, which can endogenously express each polymorphic p53 protein only, encoding either the arginine 72 (R72) variant or proline 72 (P72) variant, respectively. We found that there was no significant functional difference between P72 and R72 cells in growth arrest or apoptosis as a representative function of p53. In the comprehensive analysis, the expression pattern of the common p53 target genes, including cell cycle arrest or apoptosis, was also increased regardless of the polymorphic p53 codon 72 status, whereas the expression pattern involved in metabolism was decreased and more significant in R72 than in P72 cells. This study noted that polymorphic p53 codon 72 differentially regulated the functional categories of metabolism and not the pathways that determine cell fate, such as growth arrest and apoptosis in cells exposed to genotoxic stress.

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Güttler, Antje, Claus Weinholdt, Elisabeth Ruff, Judith Reidt, Elisa Darnstaedt, Alicia Wildemann, Marina Petrenko i in. "SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells". Cells 12, nr 1 (31.12.2022): 177. http://dx.doi.org/10.3390/cells12010177.

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Betulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for novel treatment concepts. Our analyses showed enhanced cytotoxicity and radiosensitization under hypoxic conditions in human breast cancer cells. So far, the underlying mechanisms are unknown. Therefore, we investigated the BA-treated human breast cancer cell lines MDA-MB-231 and MCF-7 under normoxic and hypoxic conditions based on microarray technology. Hypoxia and BA regulated a variety of genes in both breast cancer cell lines. KEGG pathway analysis identified an enrichment of the p53 pathway in MCF-7 cells (wtp53) under hypoxia. In MDA-MB-231 cells (mtp53) an additional BA incubation was required to activate the p53 signaling pathway. Fourteen down-regulated and up-regulated genes of the p53 pathway were selected for further validation via qRT-PCR in a panel of five breast cancer cell lines. The stress-induced gene Sestrin-2 (SESN2) was identified as one of the most strongly up-regulated genes after BA treatment. Knockdown of SESN2 enhanced BA-induced ROS production, DNA damage, radiosensitivity and reduced autophagy in breast cancer cells. Our results identified SESN2 as an important target to enhance the radiobiological and anti-tumor effects of BA on breast cancer cells.

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Choisy-Rossi, Caroline, Philippe Reisdorf i Elisheva Yonish-Rouach. "Mechanisms of p53-induced apoptosis: in search of genes which are regulated during p53-mediated cell death". Toxicology Letters 102-103 (grudzień 1998): 491–96. http://dx.doi.org/10.1016/s0378-4274(98)00238-0.

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Taylor, Alison M., Jessica M. Humphries, Richard M. White, Ryan D. Murphey, Caroline E. Burns i Leonard I. Zon. "p53 Dependent and Dose Dependent Effects of Rps29 Mutation In the Zebrafish Embryo." Blood 116, nr 21 (19.11.2010): 1170. http://dx.doi.org/10.1182/blood.v116.21.1170.1170.

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Abstract Abstract 1170 Diamond Blackfan anemia (DBA) is a rare congenital disease characterized by red cell aplasia and craniofacial abnormalities. Ribosomal protein genes are often mutated in patients with this disease, but the mechanism of action is still being investigated. To elucidate the effect of mutations in ribosomal proteins, we are studying a zebrafish rps29 mutant with hematopoietic and endothelial defects. Hematopoietic stem cells (HSCs) in rps29-/- embryos are significantly decreased, as assayed by runx1 and cmyb expression. Although the aorta and posterior cardinal vein form in the mutant, intersomitic vessel formation is affected. To test whether decreased p53 levels can rescue these defects, we crossed fish with mutated p53 into the rps29 background. In rps29-/-;p53-/- embryos, the vascular and HSC phenotypes are rescued, demonstrating that p53 may be required for these effects of rps29 knockdown. We performed a microarray comparing rps29-/- embryos and their siblings to identify genes that are differentially expressed in the mutant. Using gene set enrichment analysis (GSEA), we determined that the list of genes up-regulated in the rps29 mutant is enriched for genes up-regulated by p53 in response to irradiation. Many of the genes identified have known roles in apoptosis and stress response. We have also identified genes whose expression correlates with the number of wildtype copies of rps29. Orthopedia homolog a (otpa), which is specifically expressed in forebrain and hindbrain tissues at 24 hours post fertilization (hpf), is decreased in heterozygous siblings and further decreased in homozygous siblings. In addition, p53 knockdown partially increases otpa levels in the mutant. These data support a model where p53 activation is one of the critical downstream mediators of rps29 knockdown in several tissues, but the mechanism of tissue specificity remains unclear. The otpa phenotype suggests that regulation of some genes is dependent on rps29 levels. The zebrafish rps29 mutant will be a useful model for understanding how a decrease in ribosomal protein levels can cause specific defects in hematopoietic and neural tissues. Disclosures: Zon: FATE, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Stemgent: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Porrello, Alessandro, Maria Antonietta Cerone, Sabrina Coen, Aymone Gurtner, Giulia Fontemaggi, Letizia Cimino, Giulia Piaggio, Ada Sacchi i Silvia Soddu. "P53 Regulates Myogenesis by Triggering the Differentiation Activity of Prb". Journal of Cell Biology 151, nr 6 (11.12.2000): 1295–304. http://dx.doi.org/10.1083/jcb.151.6.1295.

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The p53 oncosuppressor protein regulates cell cycle checkpoints and apoptosis, but increasing evidence also indicates its involvement in differentiation and development. We had previously demonstrated that in the presence of differentiation-promoting stimuli, p53-defective myoblasts exit from the cell cycle but do not differentiate into myocytes and myotubes. To identify the pathways through which p53 contributes to skeletal muscle differentiation, we have analyzed the expression of a series of genes regulated during myogenesis in parental and dominant–negative p53 (dnp53)-expressing C2C12 myoblasts. We found that in dnp53-expressing C2C12 cells, as well as in p53−/− primary myoblasts, pRb is hypophosphorylated and proliferation stops. However, these cells do not upregulate pRb and have reduced MyoD activity. The transduction of exogenous TP53 or Rb genes in p53-defective myoblasts rescues MyoD activity and differentiation potential. Additionally, in vivo studies on the Rb promoter demonstrate that p53 regulates the Rb gene expression at transcriptional level through a p53-binding site. Therefore, here we show that p53 regulates myoblast differentiation by means of pRb without affecting its cell cycle–related functions.

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Okazaki, Ryuji. "Role of p53 in Regulating Radiation Responses". Life 12, nr 7 (21.07.2022): 1099. http://dx.doi.org/10.3390/life12071099.

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p53 is known as the guardian of the genome and plays various roles in DNA damage and cancer suppression. The p53 gene was found to express multiple p53 splice variants (isoforms) in a physiological, tissue-dependent manner. The various genes that up- and down-regulated p53 are involved in cell viability, senescence, inflammation, and carcinogenesis. Moreover, p53 affects the radioadaptive response. Given that several studies have already been published on p53, this review presents its role in the response to gamma irradiation by interacting with MDM2, NF-κB, and miRNA, as well as in the inflammation processes, senescence, carcinogenesis, and radiation adaptive responses. Finally, the potential of p53 as a biomarker is discussed.

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Machida, Yuichi J., Yuefeng Chen, Yuka Machida, Ankit Malhotra, Sukumar Sarkar i Anindya Dutta. "Targeted Comparative RNA Interference Analysis Reveals Differential Requirement of Genes Essential for Cell Proliferation". Molecular Biology of the Cell 17, nr 11 (listopad 2006): 4837–45. http://dx.doi.org/10.1091/mbc.e06-04-0340.

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Differences in the genetic and epigenetic make up of cell lines have been very useful for dissecting the roles of specific genes in the biology of a cell. Targeted comparative RNAi (TARCOR) analysis uses high throughput RNA interference (RNAi) against a targeted gene set and rigorous quantitation of the phenotype to identify genes with a differential requirement for proliferation between cell lines of different genetic backgrounds. To demonstrate the utility of such an analysis, we examined 257 growth-regulated genes in parallel in a breast epithelial cell line, MCF10A, and a prostate cancer cell line, PC3. Depletion of an unexpectedly high number of genes (25%) differentially affected proliferation of the two cell lines. Knockdown of many genes that spare PC3 (p53−) but inhibit MCF10A (p53+) proliferation induces p53 in MCF10A cells. EBNA1BP2, involved in ribosome biogenesis, is an example of such a gene, with its depletion arresting MCF10A at G1/S in a p53-dependent manner. TARCOR is thus useful for identifying cell type–specific genes and pathways involved in proliferation and also for exploring the heterogeneity of cell lines. In particular, our data emphasize the importance of considering the genetic status, when performing siRNA screens in mammalian cells.

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Fujiyama, Hiroki, Takahiro Tsuji, Kensuke Hironaka, Kazumasa Yoshida, Nozomi Sugimoto i Masatoshi Fujita. "GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity". Journal of Biochemistry 167, nr 1 (23.09.2019): 15–24. http://dx.doi.org/10.1093/jb/mvz075.

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Abstract Glutamate-rich WD40 repeat containing 1 (GRWD1) functions as a histone chaperone to promote loading of the MCM replication helicase at replication origins. GRWD1 is overexpressed in several cancer cell lines, and GRWD1 overexpression confers tumorigenic potential in human cells. However, less is known concerning its oncogenic activity. Our previous analysis showed that GRWD1 negatively regulates the tumour suppressor p53 via the RPL11-MDM2-p53 and RPL23-MDM2-p53 axes. Here, we demonstrate that GRWD1 directly interacts with p53 via the p53 DNA-binding domain. Upon DNA damage, GRWD1 downregulation resulted in increased p21 expression. Conversely, GRWD1 co-expression suppressed several p53-regulated promoters. GRWD1 interacted with the p21 and MDM2 promoters, and these interactions required p53. By using the Human Cancer Genome Atlas database, we found that GRWD1 expression levels are inversely correlated with the expression levels of some p53-target genes. Interestingly, high GRWD1 expression in combination with low expression levels of some p53-target genes was significantly correlated with poor prognosis in skin melanoma patients with wild-type p53. Taken together, our findings suggest a novel oncogenic function of GRWD1 as a transcriptional regulator of p53 and that GRWD1 might be an attractive therapeutic target and prognostic marker in cancer therapy.

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Pustylnyak, Vladimir O., Pavel D. Lisachev i Mark B. Shtark. "Expression of p53 Target Genes in the Early Phase of Long-Term Potentiation in the Rat Hippocampal CA1 Area". Neural Plasticity 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/242158.

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Gene expression plays an important role in the mechanisms of long-term potentiation (LTP), which is a widely accepted experimental model of synaptic plasticity. We have studied the expression of at least 50 genes that are transcriptionally regulated by p53, as well as other genes that are related to p53-dependent processes, in the early phase of LTP. Within 30 min after Schaffer collaterals (SC) tetanization, increases in the mRNA and protein levels of Bax, which are upregulated by p53, and a decrease in the mRNA and protein levels of Bcl2, which are downregulated by p53, were observed. The inhibition of Mdm2 by nutlin-3 increased the basal p53 protein level and rescued its tetanization-induced depletion, which suggested the involvement of Mdm2 in the control over p53 during LTP. Furthermore, nutlin-3 caused an increase in the basal expression of Bax and a decrease in the basal expression of Bcl2, whereas tetanization-induced changes in their expression were occluded. These results support the hypothesis that p53 may be involved in transcriptional regulation during the early phase of LTP. We hope that the presented data may aid in the understanding of the contribution of p53 and related genes in the processes that are associated with synaptic plasticity.

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Brodsky, Michael H., Brian T. Weinert, Garson Tsang, Yikang S. Rong, Nadine M. McGinnis, Kent G. Golic, Donald C. Rio i Gerald M. Rubin. "Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage". Molecular and Cellular Biology 24, nr 3 (1.02.2004): 1219–31. http://dx.doi.org/10.1128/mcb.24.3.1219-1231.2004.

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ABSTRACT We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member Eiger. Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.

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Shao, Wei, Zhen-Yu Hao, Yi-Fei Chen, Jun Du, Qian He, Liang-Liang Ren, Yan Gao i in. "OIP5-AS1 specifies p53-driven POX transcription regulated by TRPC6 in glioma". Journal of Molecular Cell Biology 13, nr 6 (28.01.2021): 409–21. http://dx.doi.org/10.1093/jmcb/mjab001.

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Abstract Transcription factors (TFs) control an array of expressed genes. However, the specifics of how a gene is expressed in time and space as controlled by a TF remain largely unknown. Here, in TRPC6-regulated proline oxidase 1 (POX) transcription in human glioma, we report that OIP5-AS1, a long noncoding RNA, determines the specificity of p53-driven POX expression. The OIP5-AS1/p53 complex via its 24 nucleotides binds to the POX promoter and is necessary for POX expression but not for p21 transcription. An O-site in the POX promoter to which OIP5-AS1 binds was identified that is required for OIP5-AS1/p53 binding and POX transcription. Blocking OIP5-AS1 binding to the O-site inhibits POX transcription and promotes glioma development. Thus, the OIP5-AS1/O-site module decides p53-controlled POX expression as regulated by TRPC6 and affects glioma development.

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Kishore, A. Hari, Kiran Batta, Chandrima Das, Shipra Agarwal i Tapas K. Kundu. "p53 regulates its own activator: transcriptional co-activator PC4, a new p53-responsive gene". Biochemical Journal 406, nr 3 (29.08.2007): 437–44. http://dx.doi.org/10.1042/bj20070390.

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The tumour suppressor protein p53 regulates the expression of several genes that mediate cell cycle arrest, apoptosis, DNA repair and other cellular responses. Recently, we have shown that human transcriptional co-activator PC4 is a unique activator of p53 function. In the present study, we report that PC4 is a p53-inducible gene. Bioinformatics analysis reveals multiple p53-binding sites in the PC4 promoter. We have found that indeed p53 binds to all the identified sites in vitro and in vivo with varying affinities. p53 acts as an activator of PC4 transcription. Both PC4 mRNA and protein levels increase in response to stimuli that result in p53 induction. Furthermore, PC4 enhances p53 recruitment to the PC4 promoter. Our results thus establish the first report of a positively regulated feedback loop to control p53 function.

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Dreyfus, David H., Masayuki Nagasawa, Colm A. Kelleher i Erwin W. Gelfand. "Stable expression of Epstein-Barr virus BZLF-1–encoded ZEBRA protein activates p53-dependent transcription in human Jurkat T-lymphoblastoid cells". Blood 96, nr 2 (15.07.2000): 625–34. http://dx.doi.org/10.1182/blood.v96.2.625.

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Abstract Interaction between viral proteins and tumor suppressor p53 is a common mechanism of viral pathogenesis. The Epstein-Barr virus (EBV) BZLF-1 ORF-encoded ZEBRA protein (also denoted EB1, Z, Zta) binds to p53 in vitro and has been associated with the altered transcription of p53-regulated genes in B lymphocytes and epithelial cells. In this work, Jurkat T-lymphoblastoid cells that express ZEBRA were characterized by the use of transiently transfected p53 and p53 reporter genes. Stable expression of ZEBRA was associated with the activation of p53-dependent transcription and increased p53 dependent apoptotic cell death. In Jurkat cell lines, stably expressed ZEBRA protein was apparently localized to the cell cytoplasm, in contrast to the typical nuclear localization of this protein in other cell types. Previous studies have suggested that EBV infection of T lymphocytes may contribute to the malignant transformation of T cells and the increased replication of human immunodeficiency virus. Our observations suggest a mechanism through which ZEBRA protein expressed in human T lymphocytes could alter T-cell proliferation and apoptosis during EBV infection.

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Dreyfus, David H., Masayuki Nagasawa, Colm A. Kelleher i Erwin W. Gelfand. "Stable expression of Epstein-Barr virus BZLF-1–encoded ZEBRA protein activates p53-dependent transcription in human Jurkat T-lymphoblastoid cells". Blood 96, nr 2 (15.07.2000): 625–34. http://dx.doi.org/10.1182/blood.v96.2.625.014k27_625_634.

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Interaction between viral proteins and tumor suppressor p53 is a common mechanism of viral pathogenesis. The Epstein-Barr virus (EBV) BZLF-1 ORF-encoded ZEBRA protein (also denoted EB1, Z, Zta) binds to p53 in vitro and has been associated with the altered transcription of p53-regulated genes in B lymphocytes and epithelial cells. In this work, Jurkat T-lymphoblastoid cells that express ZEBRA were characterized by the use of transiently transfected p53 and p53 reporter genes. Stable expression of ZEBRA was associated with the activation of p53-dependent transcription and increased p53 dependent apoptotic cell death. In Jurkat cell lines, stably expressed ZEBRA protein was apparently localized to the cell cytoplasm, in contrast to the typical nuclear localization of this protein in other cell types. Previous studies have suggested that EBV infection of T lymphocytes may contribute to the malignant transformation of T cells and the increased replication of human immunodeficiency virus. Our observations suggest a mechanism through which ZEBRA protein expressed in human T lymphocytes could alter T-cell proliferation and apoptosis during EBV infection.

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Li, Pingxin, Hongjie Yao, Zhiqiang Zhang, Ming Li, Yuan Luo, Paul R. Thompson, David S. Gilmour i Yanming Wang. "Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4". Molecular and Cellular Biology 28, nr 15 (27.05.2008): 4745–58. http://dx.doi.org/10.1128/mcb.01747-07.

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ABSTRACT Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression.

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