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p63 and p73 Transcriptionally Regulate Genes Involved in DNA Repair  [PDF]
Yu-Li Lin equal contributor,Shomit Sengupta equal contributor,Katherine Gurdziel,George W. Bell,Tyler Jacks,Elsa R. Flores
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000680
Abstract: The p53 family activates many of the same genes in response to DNA damage. Because p63 and p73 have structural differences from p53 and play distinct biological functions in development and metastasis, it is likely that they activate a unique transcriptional network. Therefore, we performed a genome-wide analysis using cells lacking the p53 family members after treatment with DNA damage. We identified over 100 genes involved in multiple pathways that were uniquely regulated by p63 or p73, and not p53. Further validation indicated that BRCA2, Rad51, and mre11 are direct transcriptional targets of p63 and p73. Additionally, cells deficient for p63 and p73 are impaired in DNA repair and p63+/?;p73+/? mice develop mammary tumors suggesting a novel mechanism whereby p63 and p73 suppress tumorigenesis.
The Tumor Suppressors p53, p63, and p73 Are Regulators of MicroRNA Processing Complex  [PDF]
Lakshmanane Boominathan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010615
Abstract: The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3′UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63?/? and dicer?/? mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.
Polymorphisms in the p63 and p73 genes are associated with ovarian cancer risk and clinicopathological variables  [cached]
Guan Xiao,Zhang Ning,Yin Yongshuo,Kong Beihua
Journal of Experimental & Clinical Cancer Research , 2012, DOI: 10.1186/1756-9966-31-89
Abstract: Objective p73 and p63 are two structural and functional homologs of p53, and their biological functions in cancer progression have attracted attention due to the presence of variants generated by genetic polymorphisms. Recently, three single nucleotide polymorphisms (SNPs) in the p63 and p73 genes have been associated with female reproduction. In the present study, we aimed to evaluate the relationship between these SNPs and ovarian cancer susceptibility and clinical pathology. Methods We genotyped the p63 (rs873330 [Genbank, refSNP ID] T > C [T: original base, C: mutant base]) and p73 (rs4648551 G > A and rs6695978 G > A) SNPs in ovarian cancers and healthy controls and analyzed the distributions of genotype frequencies to evaluate the association of the genotypes with the risk of ovarian cancer and the clinicopathological characteristics. Logistic regression models were applied in statistical analyses. Results Our research revealed that p73 rs6695978 G > A was significantly associated with ovarian cancer patients. Women with the A allele were at increased risk of ovarian cancer compared to carriers of the G allele (OR = 1.55; 95% CI:1.07–2.19; P = 0.003). Meanwhile, the at-risk A allele was positively related with the occurrence of mucinous ovarian cancer (OR = 3.48; 95% CI:1.15-6.83; P = 0.001), low degree of differentiation (OR = 1.87; 95% CI:1.03-3.47; P = 0.003), lymph node metastasis (OR = 1.69; 95% CI: 1.14-2.75; P = 0.010) and estrogen receptor positive (OR = 2.72; 95% CI: 1.38-4.81; P = 0.002). However, we were unable to find any associations of the polymorphisms in another two SNPs (rs4648551 G > A, rs873330 T > C) with ovarian cancer risk and clinicopathological parameters. Conclusions The p73 rs6695978 G > A polymorphism will serve as a modifier of ovarian cancer susceptibility and prognosis. Further investigations with large sample sizes and of the mechanistic relevance of p73 polymorphism will be warranted
Genome-Wide Mapping Indicates That p73 and p63 Co-Occupy Target Sites and Have Similar DNA-Binding Profiles In Vivo  [PDF]
Annie Yang,Zhou Zhu,Arminja Kettenbach,Philipp Kapranov,Frank McKeon,Thomas R. Gingeras,Kevin Struhl
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011572
Abstract: The p53 homologs, p63 and p73, share ~85% amino acid identity in their DNA-binding domains, but they have distinct biological functions.
Cellular functions of p53 and p53 gene family members p63 and p73
Nadir Ko?ak,?brahim Halil Y?ld?r?m,Seval Cing Y?ld?r?m
Dicle Medical Journal , 2011,
Abstract: p53 is a transcription factor that regulates multiple cellular processes that are also important in cellular fates such as cell cycle arrest or programmed cell death. Induction of growth arrest or cell death by p53 prevents the replication of damaged DNA and proliferation of genetically abnormal cells. Therefore, inactivation of p53 by mutation or deletion is also important in ensuring the cellular homeostasis. However, studies showed that p53 deficient mice and cells such as Saos-2 cells are maintaining their life. This situation suggests that p53-related proteins might compensate the functions of p53 in p53 deficient organisms. The identification of two p53-related proteins, p63 and p73 revealed the transcription of p53 responsive genes in p53 deficient organisms. Both p63 and p73 proteins have high homology with the p53 protein and share some of the functions of p53. In contrast to p53, p63 and p73 rarely mutated in human cancers. Here we studied to summarize the current information about the p53 and other p53-related proteins, p63 and p73 that are included into the p53 gene family.
ZEB1 Links p63 and p73 in a Novel Neuronal Survival Pathway Rapidly Induced in Response to Cortical Ischemia  [PDF]
Thai Bui, Judith Sequeira, Tong Chun Wen, Augusto Sola, Yujiro Higashi, Hisato Kondoh, Tom Genetta
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004373
Abstract: Background Acute hypoxic/ischemic insults to the forebrain, often resulting in significant cellular loss of the cortical parenchyma, are a major cause of debilitating injury in the industrialized world. A clearer understanding of the pro-death/pro-survival signaling pathways and their downstream targets is critical to the development of therapeutic interventions to mitigate permanent neurological damage. Methodology/Principal Findings We demonstrate here that the transcriptional repressor ZEB1, thought to be involved in regulating the timing and spatial boundaries of basic-Helix-Loop-Helix transactivator-mediated neurogenic determination/differentiation programs, functions to link a pro-survival transcriptional cascade rapidly induced in cortical neurons in response to experimentally induced ischemia. Employing histological, tissue culture, and molecular biological read-outs, we show that this novel pro-survival response, initiated through the rapid induction of p63, is mediated ultimately by the transcriptional repression of a pro-apoptotic isoform of p73 by ZEB1. We show further that this phylogenetically conserved pathway is induced as well in the human cortex subjected to episodes of clinically relevant stroke. Conclusions/Significance The data presented here provide the first evidence that ZEB1 induction is part of a protective response by neurons to ischemia. The stroke-induced increase in ZEB1 mRNA and protein levels in cortical neurons is both developmentally and phylogenetically conserved and may therefore be part of a fundamental cellular response to this insult. Beyond the context of stroke, the finding that ZEB1 is regulated by a member of the p53 family has implications for cell survival in other tissue and cellular environments subjected to ischemia, such as the myocardium and, in particular, tumor masses.
p63和p73的表达与苯并(a)芘致h1299和16hbe细胞dna损伤的关系  [PDF]
姜英,饶凯敏,陈曦,汪倩,刘爱林,袁晶
癌变·畸变·突变 , 2009,
Abstract: ?背景与目的:研究p63与p73的mrna表达与bap致人肺腺癌细胞(h1299)和人支气管上皮细胞(16hbe)dna损伤的关系、材料与方法:分别用不同浓度bap(8、16、32、64和128μmol/l)处理h1299和16hbe两种细胞,在4h和12h时,使用相应的生化检测试剂盒分别测定细胞裂解液中mda的水平和sod、gsh-px的活性,用qrt-pcr方法测定处理后细胞的p53、p63、p73、mdm2和mdm4的mrna水平;用comet实验评价细胞dna损伤程度、结果:16、32和64μmol/lbap处理4h时,两种细胞mda水平显著性升高,sod和gsh-px活性显著性下降(p<0.05)、用bap处理h1299和16hbe细胞4h和12h时均观察到dna损伤随浓度增加而加重,且呈剂量-效应关系(p<0.01),mdm2、mdm4mrna表达水平升高(p<0.01)、不过仅在12h时p53基因mrna表达水平较对照组显著增加(p<0.01)、在4h和12h时点,仅在h1299细胞的p63和p73mrna表达增加(p<0.05)、结论:在bap致p53缺失的h1299细胞的dna损伤中,bap可能通过不依赖p53信号通路激活了p63和p73mrna的表达、
Aspectos funcionais e estruturais da concordancia verbal no português falado  [cached]
Roberto Gomes Camacho
Alfa : Revista de Linguística , 2001,
Abstract: Este trabalho examina alguns fatores lingüísticos da concordancia verbal numa amostra da variedade culta falada da cidade de S o Paulo. Os resultados mostram que a concordancia verbal, uma regra variável, mesmo na variedade padr o, é governada por condi es de natureza funcional e estrutural. De um ponto de vista funcional, observa-se supress o de pluralidade em verbos existenciais, de natureza apresentacional. De um ponto de vista estrutural, nem sempre o elemento nuclear do SN exerce o controle da concordancia, mas o termo mais adjacente ao verbo. Essas observa es conduzem a considera es mais gerais, de caráter teórico, a respeito da análise lingüística de fen menos variáveis.
The structure and cellular regulation of p73: Their implication in anticancer therapy  [PDF]
Joanna Zawacka-Pankau,Katarzyna Maleńczyk,Alicja Sznarkowska
Post?py Higieny i Medycyny Do?wiadczalnej , 2010,
Abstract: p73 protein belongs, together with p63, to the p53 family. It is a relatively poorly studied structural and functional homolog of the well-described tumor suppressor protein p53, also known as the guardian of the genome. p73 protein, like p53, becomes activated by, for example, DNA damaging agents and it targets the same promoter sequences as p53. Both proteins participate in pathways of signal transduction whose activation leads to apoptosis induction or cell-cycle arrest. Studies concerning anticancer treatment focusing on the activation of p53 have been carried out extensively for about 10 years. It appears that a similar therapeutic strategy can be successfully applied in p73 activation as well. Unlike the [i]TP53[/i] gene, the gene encoding p73 protein is rarely mutated in tumors although the protein is found to be inactive. This can become very useful when designing molecules which will selectively activate p73 and consequently induce cancer-cell death. The aim of the present study was to describe in detail the structure, function, as well as cellular regulation of p73 in light of its therapeutic potential.
p73-Binding Partners and Their Functional Significance  [PDF]
Toshinori Ozaki,Natsumi Kubo,Akira Nakagawara
International Journal of Proteomics , 2010, DOI: 10.1155/2010/283863
Abstract: p73 is one of the tumor-suppressor p53 family of nuclear transcription factor. As expected from the structural similarity between p53 and p73, p73 has a tumor-suppressive function. However, p73 was rarely mutated in human primary tumors. Under normal physiological conditions, p73 is kept at an extremely low level to allow cells normal growth. In response to a certain subset of DNA damages, p73 is induced dramatically and transactivates an overlapping set of p53-target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death. Cells undergo cell cycle arrest and/or apoptotic cell death depending on the type and strength of DNA damages. p73 is regulated largely through the posttranslational modifications such as phosphorylation and acetylation. These chemical modifications are tightly linked to direct protein-protein interactions. In the present paper, the authors describe the functional significance of the protein-protein interactions in the regulation of proapoptotic p73. 1. Introduction For a long time, p53 has been believed to be a solitary gene. This classical point of view has been challenged by a discovery of novel human p53 homologues termed p73 and p63 [1–3]. Thus, p53 family is composed of p53, p73 and p63. p73 contains an NH2-terminal transactivation domain (TA; amino acid residues 1–54), a central core sequence-specific DNA-binding domain (DB; amino acid residues 131–310), an oligomerization domain (OD; amino acid residues 345–380) and a COOH-terminal sterile α motif (SAM; amino acid residues 484–549) domain [1]. Among them, the central core sequence-specific DNA-binding domain is highly conserved (more than 60% amino acid sequence identity) across the family, and p53 lacks the COOH-terminal SAM domain which is involved in the protein-protein interaction [4]. As expected from the structural similarity between p53 and p73, p73 has an ability to transactivate an overlapping set of p53-target genes implicated in cell cycle arrest and/or apoptotic cell death such as p21WAF1, MDM2, BAX, PUMA, and NOXA [5–7]. Indeed, forced expression of p73 induced cell cycle arrest and/or apoptotic cell death in certain cancerous cells [1, 8, 9]. Since p73 was mapped at human chromosome 1p36.3 where genomic aberrations are frequently observed in a variety of tumors [10–14], it is likely that p73 could be one of the classical Knudson-type tumor-suppressor genes. To address this issue, the extensive mutation search for p73 was carried out. In a sharp contrast to p53 bearing loss of-function mutations in 50% of human tumors [15, 16], p73 was
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