Journal articles: 'P53 Genes'

1

Keegan, Lunec, and Neal. "p53 and p53-regulated genes in bladder cancer." BJU International 82, no. 5 (November 1998): 710–20. http://dx.doi.org/10.1046/j.1464-410x.1998.00822.x.

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Shu, Kun-Xian, Biao Li, and Li-Xiang Wu. "The p53 network: p53 and its downstream genes." Colloids and Surfaces B: Biointerfaces 55, no. 1 (March 2007): 10–18. http://dx.doi.org/10.1016/j.colsurfb.2006.11.003.

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3

Klingler, H. Christoph. "p53 and p53 regulated genes in bladder cancer [review]." Current Opinion in Urology 9, no. 2 (March 1999): 172. http://dx.doi.org/10.1097/00042307-199903000-00015.

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4

Li, Yuwen, Jiao Liu, Nathan McLaughlin, Dimcho Bachvarov, Zubaida Saifudeen, and Samir S. El-Dahr. "Genome-wide analysis of the p53 gene regulatory network in the developing mouse kidney." Physiological Genomics 45, no. 20 (October 15, 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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Xu, H., and M. R. El-Gewely. "P53 network — its downstream regulated genes." Biochemical Society Transactions 28, no. 5 (October 1, 2000): A227. http://dx.doi.org/10.1042/bst028a227a.

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BOONMARS, T., Z. WU, I. NAGANO, and Y. TAKAHASHI. "What is the role of p53 during the cyst formation of Trichinella spiralis? A comparable study between knockout mice and wild type mice." Parasitology 131, no. 5 (July 11, 2005): 705–12. http://dx.doi.org/10.1017/s0031182005008036.

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During the cyst formation of Trichinella spiralis, the infected muscle cell undergoes basophilic change and apoptosis, which results in nurse cell formation. This study revealed expression kinetics of some apoptosis genes such as p53 and its closely related genes (tumor suppressor genes p53, p53; mouse double minute 2, MDM2; cyclin-dependent kinase inhibitor p21, p21waf). RT-PCR (reverse transcription polymerase chain reaction) results showed that these genes were temporarily expressed in the infected muscles during the cyst formation period, but not in normal muscles (or very low if any), which suggested the involvement of these apoptosis genes in the nurse cell formation. Cysts and neighbouring muscle cells were separately collected and RT-PCR was performed, which suggested that p53 was expressed in the cysts. An immunocytochemical study showed that p53 was expressed in the nucleoplasm of basophilic cell in the cyst and Trichinella larvae, which suggested involvement of these apoptosis genes in the nurse cell formation. The same p53 expression kinetic study was performed on p53 knockout mice. The knockout mice did not express p53 genes, but expressed the other apoptosis genes in the same kinetics with only minor exceptions, suggesting that the expressions of these genes during the cyst formation were more or less p53-independent. There were no differences in the number and morphology of the cysts between the knockout mice and wild type mice. Thus apoptosis seen during the Trichinella cyst formation can be operated in the presence or absence of p53.

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Hannemann, Holger, Kyle Rosenke, John M. O'Dowd, and Elizabeth A. Fortunato. "The Presence of p53 Influences the Expression of Multiple Human Cytomegalovirus Genes at Early Times Postinfection." Journal of Virology 83, no. 9 (February 18, 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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Friedlander, P., Y. Haupt, C. Prives, and M. Oren. "A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis." Molecular and Cellular Biology 16, no. 9 (September 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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9

Bruins, Wendy, Oskar Bruning, Martijs J. Jonker, Edwin Zwart, Tessa V. van der Hoeven, Jeroen L. A. Pennings, Han Rauwerda, Annemieke de Vries, and Timo M. Breit. "The Absence of Ser389 Phosphorylation in p53 Affects the Basal Gene Expression Level of Many p53-Dependent Genes and Alters the Biphasic Response to UV Exposure in Mouse Embryonic Fibroblasts." Molecular and Cellular Biology 28, no. 6 (January 14, 2008): 1974–87. http://dx.doi.org/10.1128/mcb.01610-07.

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ABSTRACT Phosphorylation is important in p53-mediated DNA damage responses. After UV irradiation, p53 is phosphorylated specifically at murine residue Ser389. Phosphorylation mutant p53.S389A cells and mice show reduced apoptosis and compromised tumor suppression after UV irradiation. We investigated the underlying cellular processes by time-series analysis of UV-induced gene expression responses in wild-type, p53.S389A, and p53−/− mouse embryonic fibroblasts. The absence of p53.S389 phosphorylation already causes small endogenous gene expression changes for 2,253, mostly p53-dependent, genes. These genes showed basal gene expression levels intermediate to the wild type and p53−/−, possibly to readjust the p53 network. Overall, the p53.S389A mutation lifts p53-dependent gene repression to a level similar to that of p53−/− but has lesser effect on p53-dependently induced genes. In the wild type, the response of 6,058 genes to UV irradiation was strictly biphasic. The early stress response, from 0 to 3 h, results in the activation of processes to prevent the accumulation of DNA damage in cells, whereas the late response, from 12 to 24 h, relates more to reentering the cell cycle. Although the p53.S389A UV gene response was only subtly changed, many cellular processes were significantly affected. The early response was affected the most, and many cellular processes were phase-specifically lost, gained, or altered, e.g., induction of apoptosis, cell division, and DNA repair, respectively. Altogether, p53.S389 phosphorylation seems essential for many p53 target genes and p53-dependent processes.

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Abramowitz, Julia, Tzahi Neuman, Riki Perlman, and Dina Ben-Yehuda. "The P53 Pathway Is Inactive in Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 5122. http://dx.doi.org/10.1182/blood.v120.21.5122.5122.

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Abstract Abstract 5122 The pathway controlled by the p53 tumor-suppressor protein is altered in most, if not all, human cancers and the TP53 gene is mutated in half of all human tumors. Such mutations are rare in human hematological malignancies, leading to the assumption that the p53 pathway is inactivated by alternative mechanisms. However, to date, the state of activity of the p53 pathway in hematological malignancies is not well understood. We investigated the functional status of the p53 pathway in Acute Myeloid Leukemia (AML) patients, particularly in patients with cytogenetically normal AML (CN-AML) and patients with Acute Promyelocytic Leukemia (APL). We performed bioinformatic analysis of p53 pathway-related gene expression. For this purpose, we first assembled a list that, to the best of our knowledge, is the most comprehensive list to date of genes related to the p53 pathway. The list consists of 1153 p53 pathway-related genes: 916 p53-related genes and 582 partially overlapping genes related to important components of the p53 pathway (Mdm2, Mdmx, Puma, Slug and Chk2). The list of p53 pathway-related genes was constructed based on gene and protein web databases and literature search. Only genes with proven biochemical relationships to the p53 pathway were included. Publically available Affymetrix gene expression array data was analyzed which included 290 CN-AML and 34 APL patients at diagnosis in comparison to 63 normal bone marrow (nBM) samples. Differentially expressed genes (DEGs) were identified out of 1153 p53 pathway-related genes using a linear statistical model that produced gene expression contrasts between leukemic samples and nBM. Study effect differences were also corrected by this model. One hundred forty seven DEGs were identified in CN-AML and 172 in APL (fold change>2. 8, p value<0. 01). We found a significant over-representation of p53 pathway related DEGs above the genomic background in both leukemias. Our analysis demonstrated homogeneity of gene expression in APL patients and discovered that CN-AML patients were further divided into 3 sub-groups by hierarchical clustering analysis. Most of the DEGs were down regulated both in CN-AML (108/147) and in APL (135/172) patients. We analyzed the DEGs and concluded that in both leukemias there was no p53-dependent induction of canonical cell cycle arrest genes, canonical pro-apoptotic genes, p53-related antioxidant defense genes, DNA damage repair genes and anti-glycolysis genes. We compared our bioinformatic results to gene expression signatures related to p53 activation by various stimuli from the literature. This analysis demonstrated that p53 protein did not exert transcriptional activation of the majority of its target genes in CN-AML and APL, implying that p53 pathway is not activated in these leukemias. We found downregulation of p300, PCAF and CARM1 genes in patient samples compared to nBM. Deregulation of these genes points to decreased acetylation and methylation of the p53 protein that can result in the inhibition of p53 transcriptional activity. We examined protein levels of p53 and its main inhibitors Mdmx and Mdm2 by immunohistochemistry in 25 CN-AML and 23 APL patients in comparison to 36 nBM biopsies. We found that the fraction of cells expressing p53, Mdmx and Mdm2 proteins was significantly higher in leukemias (70–90%) compared to nBM (10–30%). However, the intensity of Mdm2 staining was not elevated in leukemic blasts compared to nBM and p53 levels were similarly low in both nBM and leukemias. Importantly, Mdmx protein level was significantly upregulated in leukemia cells, offering an explanation for inhibition of p53 transcriptional activity in leukemia. The increased level of Mdmx protein together with low levels of p53 protein is in agreement with inhibition of p53 transcriptional activity in CN-AML and APL demonstrated by our bioinformatic analysis. Inactivation of p53 pathway shown here may be one of the important leukomogenic events in AML development. Importantly, gene expression and thus the functional status of p53 pathway is very similar in CN-AML and APL patients compared to nBM, despite the different underlying molecular etiology of these diseases. This finding may have important therapeutic implications in that similar reactivation of the p53 pathway may be a therapeutic modality applicable to these two biologically different types of leukemia. Disclosures: No relevant conflicts of interest to declare.

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Szak, Suzanne T., Deborah Mays, and Jennifer A. Pietenpol. "Kinetics of p53 Binding to Promoter Sites In Vivo." Molecular and Cellular Biology 21, no. 10 (May 15, 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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Frew, Ian J., Ross A. Dickins, Andrew R. Cuddihy, Merci Del Rosario, Christoph Reinhard, Matthew J. O'Connell, and David D. L. Bowtell. "Normal p53 Function in Primary Cells Deficient for Siah Genes." Molecular and Cellular Biology 22, no. 23 (December 1, 2002): 8155–64. http://dx.doi.org/10.1128/mcb.22.23.8155-8164.2002.

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ABSTRACT Overexpression studies have suggested that Siah1 proteins may act as effectors of p53-mediated cellular responses and as regulators of mitotic progression. We have tested these hypotheses using Siah gene knockout mice. Siah1a and Siah1b were not induced by activation of endogenous p53 in tissues, primary murine embryonic fibroblasts (MEFs) or thymocytes. Furthermore, primary MEFs lacking Siah1a, Siah1b, Siah2, or both Siah2 and Siah1a displayed normal cell cycle progression, proliferation, p53-mediated senescence, and G1 phase cell cycle arrest. Primary thymocytes deficient for Siah1a, Siah2, or both Siah2 and Siah1a, E1A-transformed MEFs lacking Siah1a, Siah1b, or Siah2, and Siah1b-null ES cells all underwent normal p53-mediated apoptosis. Finally, inhibition of Siah1b expression in Siah2 Siah1a double-mutant cells failed to inhibit cell division, p53-mediated induction of p21 expression, or cell cycle arrest. Our loss-of-function experiments do not support a general role for Siah genes in p53-mediated responses or mitosis.

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13

Nigro, J. M., R. Sikorski, S. I. Reed, and B. Vogelstein. "Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae." Molecular and Cellular Biology 12, no. 3 (March 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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Nigro, J. M., R. Sikorski, S. I. Reed, and B. Vogelstein. "Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae." Molecular and Cellular Biology 12, no. 3 (March 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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Moyer, Sydney M., Amanda R. Wasylishen, Yuan Qi, Natalie Fowlkes, Xiaoping Su, and Guillermina Lozano. "p53 drives a transcriptional program that elicits a non-cell-autonomous response and alters cell state in vivo." Proceedings of the National Academy of Sciences 117, no. 38 (September 8, 2020): 23663–73. http://dx.doi.org/10.1073/pnas.2008474117.

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Cell stress and DNA damage activate the tumor suppressor p53, triggering transcriptional activation of a myriad of target genes. The molecular, morphological, and physiological consequences of this activation remain poorly understood in vivo. We activated a p53 transcriptional program in mice by deletion ofMdm2, a gene that encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 chromatin immunoprecipitation (ChIP) sequencing, we identified a large repertoire of tissue-specific p53 genes and a common p53 transcriptional signature of seven genes, which includedMdm2but notp21. Global p53 activation caused a metaplastic phenotype in the pancreas that was missing in mice with acinar-specific p53 activation, suggesting non-cell-autonomous effects. The p53 cellular response at single-cell resolution in the intestine altered transcriptional cell state, leading to a proximal enterocyte population enriched for genes within oxidative phosphorylation pathways. In addition, a population of active CD8+ T cells was recruited. Combined, this study provides a comprehensive profile of the p53 transcriptional response in vivo, revealing both tissue-specific transcriptomes and a unique signature, which were integrated to induce both cell-autonomous and non-cell-autonomous responses and transcriptional plasticity.

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Su, Chia-Hsin, Yih-Jyh Shann, and Ming-Ta Hsu. "p53 Chromatin Epigenetic Domain Organization and p53 Transcription." Molecular and Cellular Biology 29, no. 1 (October 20, 2008): 93–103. http://dx.doi.org/10.1128/mcb.00704-08.

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ABSTRACT Epigenetic organization represents an important regulation mechanism of gene expression. In this work, we show that the mouse p53 gene is organized into two epigenetic domains. The first domain is fully unmethylated, associated with histone modifications in active genes, and organized in a nucleosome-free conformation that is deficient in H2a/H2b, whereas the second domain is fully methylated, associated with deacetylated histones, and organized in a nucleosomal structure. In mitotic cells, RNA polymerase is depleted in domain II, which is folded into a higher-order structure and is associated with H1 histone, whereas domain I conformation is preserved. Similar results were obtained for cells treated with inhibitors of associated regulatory factors. These results suggest that depletion of RNA polymerase II is the result of a physical barrier due to the folding of chromatin in domain II. The novel chromatin structure in the first domain during mitosis also suggests a mechanism for marking active genes in successive cell cycles.

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Krieg, Adam J., Ester M. Hammond, and Amato J. Giaccia. "Functional Analysis of p53 Binding under Differential Stresses." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7030–45. http://dx.doi.org/10.1128/mcb.00322-06.

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ABSTRACT Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.

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Porubiaková, Otília, Natália Bohálová, Alberto Inga, Natália Vadovičová, Jan Coufal, Miroslav Fojta, and Václav Brázda. "The Influence of Quadruplex Structure in Proximity to P53 Target Sequences on the Transactivation Potential of P53 Alpha Isoforms." International Journal of Molecular Sciences 21, no. 1 (December 24, 2019): 127. http://dx.doi.org/10.3390/ijms21010127.

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p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce several isoforms due to alternative splicing. p53 function is realized by binding to a specific DNA response element (RE), resulting in the transactivation of target genes. Here, we evaluated the influence of quadruplex DNA structure on the transactivation potential of full-length and N-terminal truncated p53α isoforms in a panel of S. cerevisiae luciferase reporter strains. Our results show that a G-quadruplex prone sequence is not sufficient for transcription activation by p53α isoforms, but the presence of this feature in proximity to a p53 RE leads to a significant reduction of transcriptional activity and changes the dynamics between co-expressed p53α isoforms.

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Uxa, Sigrid, Stephan H. Bernhart, Christina F. S. Mages, Martin Fischer, Robin Kohler, Steve Hoffmann, Peter F. Stadler, Kurt Engeland, and Gerd A. Müller. "DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation." Nucleic Acids Research 47, no. 17 (August 10, 2019): 9087–103. http://dx.doi.org/10.1093/nar/gkz635.

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Abstract Most human cancers acquire mutations causing defects in the p53 signaling pathway. The tumor suppressor p53 becomes activated in response to genotoxic stress and is essential for arresting the cell cycle to facilitate DNA repair or to initiate apoptosis. p53-induced cell cycle-arrest is mediated by expression of the CDK inhibitor p21WAF1/Cip1, which prevents phosphorylation and inactivation of the pocket proteins RB, p130, and p107. In a hypophosphorylated state, pocket proteins bind to E2F factors forming RB-E2F and DREAM transcriptional repressor complexes. Here, we analyze the influence of RB and DREAM on p53-induced gene repression and cell-cycle arrest. We show that abrogation of DREAM function by knockout of the DREAM component LIN37 results in a reduced repression of cell-cycle genes. We identify the genes repressed by the p53-DREAM pathway and describe a set of genes that is downregulated by p53 independent of LIN37/DREAM. Most strikingly, p53-dependent repression of cell-cycle genes is completely abrogated in LIN37−/−;RB−/− cells leading to a loss of the G1/S checkpoint. Taken together, we show that DREAM and RB are key factors in the p53 signaling pathway to downregulate a large number of cell-cycle genes and to arrest the cell cycle at the G1/S transition.

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Lotem, J., H. Gal, R. Kama, N. Amariglio, G. Rechavi, E. Domany, L. Sachs, and D. Givol. "Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes." Proceedings of the National Academy of Sciences 100, no. 11 (May 12, 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, and J. Kajstura. "Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death." Diabetes 50, no. 10 (October 1, 2001): 2363–75. http://dx.doi.org/10.2337/diabetes.50.10.2363.

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Buckbinder, L., R. Talbott, B. R. Seizinger, and N. Kley. "Gene regulation by temperature-sensitive p53 mutants: identification of p53 response genes." Proceedings of the National Academy of Sciences 91, no. 22 (October 25, 1994): 10640–44. http://dx.doi.org/10.1073/pnas.91.22.10640.

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El-Dahr, Samir S., and Zubaida Saifudeen. "Interactions between BdkrB2 and p53 genes in the developing kidney." Biological Chemistry 394, no. 3 (March 1, 2013): 347–51. http://dx.doi.org/10.1515/hsz-2012-0281.

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Abstract Gene-environment interactions are implicated in congenital disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Work from our laboratory demonstrates the presence of genetic interactions between the bradykinin B2 receptor (BdkrB2) and the tumor suppressor protein p53 in the developing kidney. Our studies have shown that the Bdkrb2-/- embryos exposed to gestational salt stress develop renal dysgenesis. The underlying mechanism is p53 stabilization and mediated apoptosis and repression of the terminal epithelial differentiation program. We also uncovered a novel functional cross-talk between p53 and BdkrB2. Thus, while BdkrB2 is a target for p53-mediated transcriptional activation, BdkrB2 inactivation results in the upregulation of checkpoint kinase 1 (Chk1) levels, thus potentiating phosphorylation of p53 on Ser23 by Chk1, an essential step in the pathway leading to renal dysgenesis in salt-stressed BdkrB2-/- mutant mice. Future studies will now focus on defining how this G-protein-coupled receptor is coupled to the activation of p53, a tumor suppressor gene that is mutated in more than 50% of all human cancers.

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Mattar, Rejane, Suely Nonogaki, Cleonice Silva, Venancio Alves, and Joaquim J. Gama-Rodrigues. "P53 and Rb tumor suppressor gene alterations in gastric cancer." Revista do Hospital das Clínicas 59, no. 4 (2004): 172–80. http://dx.doi.org/10.1590/s0041-87812004000400004.

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Inactivation of tumor suppressor genes has been frequently observed in gastric carcinogenesis. Our purpose was to study the involvement of p53, APC, DCC, and Rb genes in gastric carcinoma. METHOD: Loss of heterozygosity of the p53, APC, DCC and Rb genes was studied in 22 gastric cancer tissues using polymerase chain reaction; single-strand conformation polymorphism of the p53 gene exons 5-6 and exons 7-8 was studied using 35S-dATP, and p53 expression was detected using a histological immunoperoxidase method with an anti-p53 clone. RESULTS AND DISCUSSION: No loss of heterozygosity was observed in any of these tumor suppressor genes; homozygous deletion was detected in the Rb gene in 23% (3/13) of the cases of intestinal-type gastric carcinoma. Eighteen (81.8%) cases showed band mobility shifts in exons 5-6 and/or 7-8 of the p53 gene. The presence of the p53 protein was positive in gastric cancer cells in 14 cases (63.6%). Normal gastric mucosa showed negative staining for p53; thus, the immunoreactivity was likely to represent mutant forms. The correlation of band mobility shift and the immunoreactivity to anti-p53 was not significant (P = .90). There was no correlation of gene alterations with the disease severity. CONCLUSIONS: The inactivation of Rb and p53 genes is involved in gastric carcinogenesis in our environment. Loss of the Rb gene observed only in the intestinal-type gastric cancer should be further evaluated in association with Helicobacter pylori infection. The p53 gene was affected in both intestinal and diffuse histological types of gastric cancer.

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Wylie, Annika, Amanda E. Jones, Alejandro D'Brot, Wan-Jin Lu, Paula Kurtz, John V. Moran, Dinesh Rakheja, et al. "p53 genes function to restrain mobile elements." Genes & Development 30, no. 1 (December 23, 2015): 64–77. http://dx.doi.org/10.1101/gad.266098.115.

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Hergenhahn, Manfred, Jun-Li Luo, and Monica Hollstein. "p53 Designer Genes for the Modern Mouse." Cell Cycle 3, no. 6 (June 2004): 736–39. http://dx.doi.org/10.4161/cc.3.6.890.

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Merlo, Paola, Bess Frost, Shouyong Peng, Yawei J. Yang, Peter J. Park, and Mel Feany. "p53 prevents neurodegeneration by regulating synaptic genes." Proceedings of the National Academy of Sciences 111, no. 50 (December 1, 2014): 18055–60. http://dx.doi.org/10.1073/pnas.1419083111.

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Yu, J., L. Zhang, P. M. Hwang, C. Rago, K. W. Kinzler, and B. Vogelstein. "Identification and classification of p53-regulated genes." Proceedings of the National Academy of Sciences 96, no. 25 (December 7, 1999): 14517–22. http://dx.doi.org/10.1073/pnas.96.25.14517.

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Riley, Todd, Eduardo Sontag, Patricia Chen, and Arnold Levine. "Transcriptional control of human p53-regulated genes." Nature Reviews Molecular Cell Biology 9, no. 5 (May 2008): 402–12. http://dx.doi.org/10.1038/nrm2395.

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Fischer, M. "Census and evaluation of p53 target genes." Oncogene 36, no. 28 (March 13, 2017): 3943–56. http://dx.doi.org/10.1038/onc.2016.502.

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Gazitt, Yair, Cagla Akay, and Fatih Kircelli. "Global Gene Expression Changes during Arsenic Trioxide -Induced Apoptosis in Myeloma Cell Lines Expressing Mutant or w.t p53." Blood 106, no. 11 (November 16, 2005): 4351. http://dx.doi.org/10.1182/blood.v106.11.4351.4351.

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Abstract Arsenic trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia and is being tested in phase II studies in various types of hematological malignancies and solid tumors. We have previously shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging primarily the intrinsic apoptotic pathway in cells expressing w.t. p53. In contrast, in cells expressing mutant p53, both the intrinsic and extrinsic apoptotic pathways are engaged. These findings were further supported by a recent study using a p53 temperature sensitive (p53Ts) mutant cell line, BRK, expressing w.t. p53 at 32°C and mutant p53 phenotype at 37°C (Akay et al. Akay et al., AACR; Abstract #5344, 2005). Furthermore, myeloma cells expressing w.t. p53 transfected with SiRNA for p53 or p21 behaved like cells with mutant p53 (Kircelli et al. ASH presentation,2005). In order to identify new genes affected by ATO we used the Affymetrix Microarray technology to compare global gene expression in IM9 myeloma cells (w.t. p53) and U266 myeloma cells (mutant p53) following 0, 1,5 and 10 hours of treatment with ATO. We found ≥2 fold increase in gene expression by Affymetrix Microarray Suite Software (MAS) in 94 genes at 5 h and 455 genes at 10 h with an increase in 134, at both 5 and 10 h of treatment. By similar analysis, 263 genes were decreased at 5 h and 679 genes were decreased at 10 h with 204 genes decreased at both time points. Similar analysis with GeneSpring (GS) software revealed an increase in 202 genes and a decrease in 233 genes at both 5 and 10 h. Combination of the 2 analysis methods yielded 90 consistent increasers and 64 consistent decreasers. A great number of these genes in whom we detected changes in this study are genes that were previously identified by us and by others using Western immunoblotting. In addition, we observed differential effect of ATO in IM9 and U266 myeloma cells in apoptosis-related genes (HRK, BID, MCL1); cell cycle-related genes (GADD45, Cyclin D1, cyclin D2 and cyclin D3); signal transduction proteins (ERK, NFkB, ATM, ATR, CHK2, TRAILR2, TNF-R5/6 and VEGF); in chaperon proteins; cyclophyllin B; SAT, ToPoIIA and others. Systematic validation of these changes on the protein levels is ongoing.

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Gridasova, Anastasia A., and R. William Henry. "The p53 Tumor Suppressor Protein Represses Human snRNA Gene Transcription by RNA Polymerases II and III Independently of Sequence-Specific DNA Binding." Molecular and Cellular Biology 25, no. 8 (April 15, 2005): 3247–60. http://dx.doi.org/10.1128/mcb.25.8.3247-3260.2005.

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ABSTRACT Human U1 and U6 snRNA genes are transcribed by RNA polymerases II and III, respectively. While the p53 tumor suppressor protein is a general repressor of RNA polymerase III transcription, whether p53 regulates snRNA gene transcription by RNA polymerase II is uncertain. The data presented herein indicate that p53 is an effective repressor of snRNA gene transcription by both polymerases. Both U1 and U6 transcription in vitro is repressed by recombinant p53, and endogenous p53 occupancy at these promoters is stimulated by UV light. In response to UV light, U1 and U6 transcription is strongly repressed. Human U1 genes, but not U6 genes, contain a high-affinity p53 response element located within the core promoter region. Nonetheless, this element is not required for p53 repression and mutant p53 molecules that do not bind DNA can maintain repression, suggesting a reliance on protein interactions for p53 promoter recruitment. Recruitment may be mediated by the general transcription factors TATA-box binding protein and snRNA-activating protein complex, which interact well with p53 and function for both RNA polymerase II and III transcription.

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Bian, J., and Y. Sun. "Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter." Molecular and Cellular Biology 17, no. 11 (November 1997): 6330–38. http://dx.doi.org/10.1128/mcb.17.11.6330.

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p53, a tumor suppressor and a transcription factor, has been shown to transcriptionally activate the expression of a number of important genes involved in the regulation of cell growth, DNA damage, angiogenesis, and apoptosis. In a computer search for other potential p53 target genes, we identified a perfect p53 binding site in the promoter of the human type IV collagenase (also called 72-kDa gelatinase or matrix metalloproteinase 2 [MMP-2]) gene. This p53 binding site was found to specifically bind to p53 protein in a gel shift assay. Transcription assays with luciferase reporters driven by the promoter or enhancer of the type IV collagenase gene revealed that (i) activation of the promoter activity is p53 binding site dependent in p53-positive cells but not in p53-negative cells and (ii) wild-type p53, but not p53 mutants commonly found in human cancers, transactivates luciferase expression driven by the type IV collagenase promoter as well as by a p53 site-containing enhancer element in the promoter. Significantly, expression of the endogenous type IV collagenase is also under the control of p53. Treatment of U2-OS cells, a wild-type p53-containing osteogenic sarcoma line, with a common p53 inducer, etoposide, induced p53 DNA binding and transactivation activities in a time-dependent manner. Induction of type IV collagenase expression followed the p53 activation pattern. No induction of type IV collagenase expression can be detected under the same experimental conditions in p53-negative Saos-2 cells. All these in vitro and in vivo assays strongly suggest that the type IV collagenase gene is a p53 target gene and that its expression is subject to p53 regulation. Our finding links p53 to a member of the MMP genes, a family of genes implicated in trophoblast implantation, wound healing, angiogenesis, arthritis, and tumor cell invasion. p53 may regulate these processes by upregulating expression of type IV collagenase.

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Wang, Chao, Cui Rong Teo, and Kanaga Sabapathy. "p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?" International Journal of Molecular Sciences 21, no. 4 (February 17, 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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Tassabehji, Nadine M., Jacob W. Vanlandingham, and 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, no. 10 (November 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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Brázda, Václav, and Miroslav Fojta. "The Rich World of p53 DNA Binding Targets: The Role of DNA Structure." International Journal of Molecular Sciences 20, no. 22 (November 9, 2019): 5605. http://dx.doi.org/10.3390/ijms20225605.

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The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes. Most p53 target genes contain so-called p53 response elements in their promoters, consisting of 20 bp long canonical consensus sequences. Compared to other transcription factors, which usually bind to one concrete and clearly defined DNA target, the p53 consensus sequence is not strict, but contains two repeats of a 5′RRRCWWGYYY3′ sequence; therefore it varies remarkably among target genes. Moreover, p53 binds also to DNA fragments that at least partially and often completely lack this consensus sequence. p53 also binds with high affinity to a variety of non-B DNA structures including Holliday junctions, cruciform structures, quadruplex DNA, triplex DNA, DNA loops, bulged DNA, and hemicatenane DNA. In this review, we summarize information of the interactions of p53 with various DNA targets and discuss the functional consequences of the rich world of p53 DNA binding targets for its complex regulatory functions.

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Elston, Rebecca, and Gareth J. Inman. "Crosstalk between p53 and TGF-β Signalling." Journal of Signal Transduction 2012 (March 28, 2012): 1–10. http://dx.doi.org/10.1155/2012/294097.

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Wild-type p53 and TGF-β are key tumour suppressors which regulate an array of cellular responses. TGF-β signals in part via the Smad signal transduction pathway. Wild-type p53 and Smads physically interact and coordinately induce transcription of a number of key tumour suppressive genes. Conversely mutant p53 generally subverts tumour suppressive TGF-β responses, diminishing transcriptional activation of key TGF-β target genes. Mutant p53 can also interact with Smads and this enables complex formation with the p53 family member p63 and blocks p63-mediated activation of metastasis suppressing genes to promote tumour progression. p53 and Smad function may also overlap during miRNA biogenesis as they can interact with the same components of the Drosha miRNA processing complex to promote maturation of specific subsets of miRNAs. This paper investigates the crosstalk between p53 and TGF-β signalling and the potential roles this plays in cancer biology.

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Alzhanova, Dina, Kathleen Corcoran, Aubrey G. Bailey, Kristin Long, Sharon Taft-Benz, Rachel L. Graham, Grant S. Broussard, et al. "Novel modulators of p53-signaling encoded by unknown genes of emerging viruses." PLOS Pathogens 17, no. 1 (January 7, 2021): e1009033. http://dx.doi.org/10.1371/journal.ppat.1009033.

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The p53 transcription factor plays a key role both in cancer and in the cell-intrinsic response to infections. The ORFEOME project hypothesized that novel p53-virus interactions reside in hitherto uncharacterized, unknown, or hypothetical open reading frames (orfs) of human viruses. Hence, 172 orfs of unknown function from the emerging viruses SARS-Coronavirus, MERS-Coronavirus, influenza, Ebola, Zika (ZIKV), Chikungunya and Kaposi Sarcoma-associated herpesvirus (KSHV) were de novo synthesized, validated and tested in a functional screen of p53 signaling. This screen revealed novel mechanisms of p53 virus interactions and two viral proteins KSHV orf10 and ZIKV NS2A binding to p53. Originally identified as the target of small DNA tumor viruses, these experiments reinforce the notion that all viruses, including RNA viruses, interfere with p53 functions. These results validate this resource for analogous systems biology approaches to identify functional properties of uncharacterized viral proteins, long non-coding RNAs and micro RNAs.

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Liu, Hanshao, Hoi Chin Hew, Zheng-Guang Lu, Tomoko Yamaguchi, Yoshio Miki, and Kiyotsugu Yoshida. "DNA damage signalling recruits RREB-1 to the p53 tumour suppressor promoter." Biochemical Journal 422, no. 3 (August 27, 2009): 543–51. http://dx.doi.org/10.1042/bj20090342.

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Transcriptional regulation of the p53 tumour suppressor gene plays an important role in the control of the expression of various target genes involved in the DNA damage response. However, the molecular basis of this regulation remains obscure. In the present study we demonstrate that RREB-1 (Ras-responsive-element-binding protein-1) efficiently binds to the p53 promoter via the p53 core promoter element and transactivates p53 expression. Silencing of RREB-1 significantly reduces p53 expression at both the mRNA and the protein levels. Notably, disruption of RREB-1-mediated p53 transcription suppresses the expression of the p53 target genes. We also show that, upon exposure to genotoxic stress, RREB-1 controls apoptosis in a p53-dependent manner. These findings provide evidence that RREB-1 participates in modulating p53 transcription in response to DNA damage.

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Ludwig, R. L., S. Bates, and K. H. Vousden. "Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function." Molecular and Cellular Biology 16, no. 9 (September 1996): 4952–60. http://dx.doi.org/10.1128/mcb.16.9.4952.

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The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

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Lee, Su-Been, Sangsun Lee, Ji-Young Park, Sun-Young Lee, and Ho-Shik Kim. "Induction of p53-Dependent Apoptosis by Prostaglandin A2." Biomolecules 10, no. 3 (March 24, 2020): 492. http://dx.doi.org/10.3390/biom10030492.

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Prostaglandin (PG) A2, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA2 has been reported to cause activation of apoptosis by altering the expression of apoptosis-related genes, the role of p53, one of the most critical pro-apoptotic genes, on PGA2-induced apoptosis has not been clarified yet. To address this issue, we compared the apoptosis in HCT116 p53 null cells (HCT116 p53-/-) to that in HCT116 cells containing the wild type p53 gene. Cell death induced by PGA2 was associated with phosphorylation of histone H2A variant H2AX (H2AX), activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase 1 in HCT116 cells. Induction of apoptosis in PGA2-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PGA2 induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as p21WAF1, PUMA, BAX, NOXA, and DR5 occurred. Besides, pretreatment of pifithrin-α (PFT-α), a chemical inhibitor of p53’s transcriptional activity, interfered with the induction of apoptosis in PGA2-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PGA2-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of DR5 expression by RNA interference, suppressed PGA2-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PGA2 induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PGA2 in HCT116 p53-/- cells was also associated with phosphorylation of H2AX but was not inhibited by either PFT-α or NU7441. Collectively, these results suggest the following. PGA2 may induce p53-dependent apoptosis in which DNA-PK activates p53, and DR5, a transcriptional target of p53, plays a pivotal role in HCT116 cells. In contrast to apoptosis in HCT116 cells, PGA2 may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cells

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Tao, Zhengchao, and Liting Qian. "Effect of p53 gene transfection on human hepatocarcinoma cells' sensitivity to irradiation." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22018-e22018. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22018.

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e22018 Background: Several studies demonstrated that p53 gene transfection enhanced the anti-tumor effects of radiotherapy. This study is to investigate whether p53 gene transfection can increase the radiosensitivity of liver tumor cells. Methods: Liver tumor cell lines, HepG2 (with wild type p53 genes) and PLC/PRF/5 (with mutant p53 genes), were separately transfected with recombinant adenoviral human p53 gene (rAdp53) and adenoviral enhance green fluorescent protein gene (AdEGFP), forming 4 types of cells: HepG2 transfected with rAdp53, HepG2 with AdEGFP, PLC/PRF/5 with rAdp53, and PLC/PRF/5 with AdEGFP. The transfected and untransfected HepG2 and PLC/PRF/5 cells were irradiated with 6MV-X at doses of 0, A2, A4, A6, A8, A and 10 Gy. After exposition to radiation, cell survival, clonogenic capacity, and apoptosis were analyzed. The effect differences between cell types were analyzed using statistical methods of pairwise group comparisons and mixed effect model. Results: After exposing irradiation, all the cells’ survival rate and clonogenic capacity decreased, and the proportion of apoptotic cell increased. These effects become stronger with increaseing dose of radiation. Between untransfected cells, radiation had a stronger effect on HepG2 cells than PLC/PRF/5 and the differences were statistically significant for all the 3 measures. The rAdp53 transfection, not the AdEGFP, significantly enhanced radiation effects on both cell lines. The enhanced effects on PLC/PRF/5 cells were significantly stronger then the enhanced effects on HepG2 cells. Conclusions: PLC/PRF/5 cells with mutant p53 genes were more resistant to radiation then HepG2 with wide type of p53 genes. The rAd-P53 transfection could enhance radiosensitivity of both cell lines, but the enhanced effect on PLC/PRF/5 cells with mutant p53 gene was stronger than HepG2 with wide type of p53 genes.

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Apostolidis, Pani A., Stephan Lindsey, William M. Miller, and Eleftherios T. Papoutsakis. "Proposed megakaryocytic regulon of p53: the genes engaged to control cell cycle and apoptosis during megakaryocytic differentiation." Physiological Genomics 44, no. 12 (June 15, 2012): 638–50. http://dx.doi.org/10.1152/physiolgenomics.00028.2012.

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During endomitosis, megakaryocytes undergo several rounds of DNA synthesis without division leading to polyploidization. In primary megakaryocytes and in the megakaryocytic cell line CHRF, loss or knock-down of p53 enhances cell cycling and inhibits apoptosis, leading to increased polyploidization. To support the hypothesis that p53 suppresses megakaryocytic polyploidization, we show that stable expression of wild-type p53 in K562 cells (a p53-null cell line) attenuates the cells' ability to undergo polyploidization during megakaryocytic differentiation due to diminished DNA synthesis and greater apoptosis. This suggested that p53's effects during megakaryopoiesis are mediated through cell cycle- and apoptosis-related target genes, possibly by arresting DNA synthesis and promoting apoptosis. To identify candidate genes through which p53 mediates these effects, gene expression was compared between p53 knock-down (p53-KD) and control CHRF cells induced to undergo terminal megakaryocytic differentiation using microarray analysis. Among substantially downregulated p53 targets in p53-KD megakaryocytes were cell cycle regulators CDKN1A (p21) and PLK2, proapoptotic FAS, TNFRSF10B, CASP8, NOTCH1, TP53INP1, TP53I3, DRAM1, ZMAT3 and PHLDA3, DNA-damage-related RRM2B and SESN1, and actin component ACTA2, while antiapoptotic CKS1B, BCL2, GTSE1, and p53 family member TP63 were upregulated in p53-KD cells. Additionally, a number of cell cycle-related, proapoptotic, and cytoskeleton-related genes with known functions in megakaryocytes but not known to carry p53-responsive elements were differentially expressed between p53-KD and control CHRF cells. Our data support a model whereby p53 expression during megakaryopoiesis serves to control polyploidization and the transition from endomitosis to apoptosis by impeding cell cycling and promoting apoptosis. Furthermore, we identify a putative p53 regulon that is proposed to orchestrate these effects.

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Caelles, Carme, Arno Helmberg, and Michael Karin. "p53-Dependent apoptosis in the absence of transcriptional activation of p53-target genes." Nature 370, no. 6486 (July 1994): 220–23. http://dx.doi.org/10.1038/370220a0.

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Panchanathan, Ravichandran, Hongzhu Liu, and Divaker Choubey. "Activation of p53 in Human and Murine Cells by DNA-Damaging Agents Differentially Regulates Aryl Hydrocarbon Receptor Levels." International Journal of Toxicology 34, no. 3 (April 15, 2015): 242–49. http://dx.doi.org/10.1177/1091581815578013.

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Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates multiple cellular processes. The anticancer drug doxorubicin (DOX) can activate AhR-mediated transcription of target genes. Because DOX in cells activates a DNA damage response involving ataxia telangiectasia-mutated (ATM)-mediated activation of p53, we investigated whether the activation of the p53 in cells by DNA-damaging agents such as DOX or bleomycin could regulate the AhR levels. Here we report that activation of p53 by DNA-damaging agents in human cells increased levels of AhR through a posttranscriptional mechanism. Accordingly, fibroblasts from ATM patients, which are defective in p53 activation, expressed reduced constitutive levels of AhR and treatment of cells with bleomycin did not appreciably increase the AhR levels. Further, activation of p53 in cells stimulated the expression of AhR target genes. In murine cells, activation of p53 reduced the levels of AhR messenger RNA and protein and reduced the expression of AhR target genes. Our observations revealed that activation of p53 in human and murine cells differentially regulates AhR levels.

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Kim, Eunjung, Jae-Young Kim, and Joo-Yong Lee. "Mathematical Modeling of p53 Pathways." International Journal of Molecular Sciences 20, no. 20 (October 18, 2019): 5179. http://dx.doi.org/10.3390/ijms20205179.

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Cells have evolved balanced systems that ensure an appropriate response to stress. The systems elicit repair responses in temporary or moderate stress but eliminate irreparable cells via apoptosis in detrimental conditions of prolonged or severe stress. The tumor suppressor p53 is a central player in these stress response systems. When activated under DNA damage stress, p53 regulates hundreds of genes that are involved in DNA repair, cell cycle, and apoptosis. Recently, increasing studies have demonstrated additional regulatory roles of p53 in metabolism and mitochondrial physiology. Due to the inherent complexity of feedback loops between p53 and its target genes, the application of mathematical modeling has emerged as a novel approach to better understand the multifaceted functions and dynamics of p53. In this review, we discuss several mathematical modeling approaches in exploring the p53 pathways.

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Zhuang, Linhan, Regina Ly, Frank Rösl, and Martina Niebler. "p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells." International Journal of Molecular Sciences 21, no. 24 (December 15, 2020): 9533. http://dx.doi.org/10.3390/ijms21249533.

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Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 E6/E7 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during E6/E7 oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., PML and YPEL3) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., DRAM1 and BNIP3) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral E6/E7-oncogenes as drivers for proliferation remained inhibited under hypoxia.

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Menendez, Daniel, Alberto Inga, and 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, no. 6 (March 15, 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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Fujiyama, Hiroki, Takahiro Tsuji, Kensuke Hironaka, Kazumasa Yoshida, Nozomi Sugimoto, and Masatoshi Fujita. "GRWD1 directly interacts with p53 and negatively regulates p53 transcriptional activity." Journal of Biochemistry 167, no. 1 (September 23, 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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Schade, Amy E., Martin Fischer, and James A. DeCaprio. "RB, p130 and p107 differentially repress G1/S and G2/M genes after p53 activation." Nucleic Acids Research 47, no. 21 (October 31, 2019): 11197–208. http://dx.doi.org/10.1093/nar/gkz961.

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Abstract Cell cycle gene expression occurs in two waves. The G1/S genes encode factors required for DNA synthesis and the G2/M genes contribute to mitosis. The Retinoblastoma protein (RB) and DREAM complex (DP, RB-like, E2F4 and MuvB) cooperate to repress all cell cycle genes during G1 and inhibit entry into the cell cycle. DNA damage activates p53 leading to increased levels of p21 and inhibition of cell cycle progression. Whether the G1/S and G2/M genes are differentially repressed by RB and the RB-like proteins p130 and p107 in response to DNA damage is not known. We performed gene expression profiling of primary human fibroblasts upon DNA damage and assessed the effects on G1/S and G2/M genes. Upon p53 activation, p130 and RB cooperated to repress the G1/S genes. In addition, in the absence of RB and p130, p107 contributed to repression of G1/S genes. In contrast, G2/M genes were repressed by p130 and p107 after p53 activation. Furthermore, repression of G2/M genes by p107 and p130 led to reduced entry into mitosis. Our data demonstrates specific roles for RB, p130-DREAM, and p107-DREAM in p53 and p21 mediated repression of cell cycle genes.

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Journal articles on the topic 'P53 Genes'

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