| tumor protein p63 | OKDB#: 1885 |
| Symbols: | TP63 | Species: | human | ||
| Synonyms: | AIS, KET, LMS, NBP, RHS, p40, p51, p63, EEC3, OFC8, p73H, p73L, SHFM4, TP53L, TP73L, p53CP, TP53CP, B(p51A), B(p51B) | Locus: | 3q28 in Homo sapiens |
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| General Comment |
Tumor protein p63 shows strong homology to the tumor suppressor p53 (191170) and the p53-related protein p73 (601990). p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis.
NCBI Summary: This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016] |
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| General function | Cell cycle regulation, Tumor suppressor, Transcription factor | ||||
| Comment | DNA Damage in Oocytes Induces a Switch of the Quality Control Factor TAp63a from Dimer to Tetramer. Deutsch GB et al. TAp63a, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63a's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63a inhibition remains unknown. Here, we show that TAp63a is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ~20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63a is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63a is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes. | ||||
| Cellular localization | Cytoplasmic, Nuclear | ||||
| Comment | |||||
| Ovarian function | Follicle endowment, Oogenesis | ||||
| Comment | The p63 C-terminus is essential for murine oocyte integrity. Lena AM et al. (2021) The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3'-end of p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency.////////////////// Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level. Coutandin D et al. (2016) Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.////////////////// DNA damage in the oocytes SACs. Macurek L et al. (2015) Maintaining the genome integrity is essential for reproduction. Long lifespan of mammalian oocytes makes them particularly vulnerable to accumulation of genetic aberrations that can eventually cause infertility or developmental disorders. As a safeguard mechanism, immature oocytes in primordial follicles are eliminated by a p63-dependent cell death following exposure to genotoxic stress. However, p63 pathway is not active in later stages of oocyte maturation and until recently it remained unclear how the germinal vesicle oocytes respond to DNA damage.////////////////// Defying DNA double strand break-induced death during prophase I meiosis by temporal TAp63a phosphorylation regulation in developing mouse oocytes. Kim DA 2014 et al. The dichotomy in DNA damage sensitivity of developing mouse oocytes during female germline development is striking. Embryonic oocytes withstand hundreds of programmed DSBs required for meiotic recombination. Post-natal immature oocytes fail to tolerate even a few DNA double strand breaks (DSBs) induced by ?-radiation treatment. TAp63a, a p53 family member, undergoes phosphorylation and mediates post-natal immature oocyte death following ?-radiation treatment, which is thought important for germline quality maintenance. Whether pre-natal meiotic oocytes tolerate DNA DSBs simply because they lack TAp63a expression is not clear. We found a significant number of oocytes in newborn mice initiate TAp63a expression and simultaneously carry meiotic DNA DSBs. However, the risk of premature death appears unlikely, because newborn oocytes strongly abate TAp63a phosphorylation induction and resist normally lethal doses of IR damage. A calyculin A-sensitive Ser/Thr phosphatase activity downregulates TAp63a phosphorylation and ATM kinase mediates phosphorylation. Possible alterations in the relative balance of these counteracting activities during development may first temper TAp63a phosphorylation and death induction during meiotic DNA DSB repair and recombination, and afterwards, implement germline quality control in later stages. Insights into inherent DNA DSB resistance mechanisms in newborn oocytes may help prevent infertility in women in need of radiation or chemotherapy. ///////////////////////// DNA Damage-Induced Primordial Follicle Oocyte Apoptosis and Loss of Fertility Require TAp63-Mediated Induction of Puma and Noxa. Kerr JB et al. Trp63, a transcription factor related to the tumor suppressor p53, is activated by diverse stimuli and can initiate a range of cellular responses. TAp63 is the predominant Trp53 family member in primordial follicle oocyte nuclei and is essential for their apoptosis triggered by DNA damage in?vivo. After ?-irradiation, induction of the proapoptotic BH3-only members Puma and Noxa was observed in primordial follicle oocytes from WT and Trp53(-/-) mice but not in those from TAp63-deficient mice. Primordial follicle oocytes from mice lacking Puma or both Puma and Noxa were protected from ?-irradiation-induced apoptosis and, remarkably, could produce healthy offspring. Hence, PUMA and NOXA are critical for DNA damage-induced, TAp63-mediated primordial follicle oocyte apoptosis. Thus, blockade of PUMA may protect fertility during cancer therapy and prevent premature menopause, improving women's health. Regulation of Fertility by the p53 Family Members. Hu W et al. The p53 family members, which consist of 3 transcription factors-p53, p63, and p73-are conserved during evolution. The p53 family proteins are involved in many important cellular functions, including tumor suppression (p53 and p73), the development of epithelial cell layers (p63), and the development of central nervous system and immune system (p73). Studies on p53-like proteins in low organisms have demonstrated that their primordial functions are to maintain the genomic integrity of germ cells and ensure faithful development and reproduction. In vertebrates, the p53 family proteins retain these functions in reproduction and at the same time have developed additional important functions in reproduction, such as the regulation of embryonic implantation (p53). p53 regulates embryonic implantation through transcriptional regulation of leukemia inhibitory factor (LIF). p63, in particular TAp63, is a main regulator to protect the fidelity of female germ cells during meiotic arrest. p73, in particular TAp73, regulates the ovary function and the quality of oocytes. Loss of p53, p63, or p73 genes in female mice leads to a significant decrease in fertility. These functions of the p53 family proteins in reproduction provide a plausible explanation for positive evolutionary selection observed in a group of single nucleotide polymorphisms and haplotypes in the p53 family genes. A better understanding of the functions of the p53 family proteins in reproduction may lead to new strategies for fertility treatment. | ||||
| Expression regulated by | LH | ||||
| Comment | Expression of p63 in the Mouse Ovary. Nakamuta N et al. Transcription factor p63, a member of the tumor suppressor p53 family, plays an important role in epithelial development, and its expression is found in many epithelial tissues. Our previous reports have shown that p63 is expressed in primordial and testicular germ cells. In this study, we investigated the expression and distribution of p63 isoforms (TAp63alpha, TAp63beta, TAp63gamma, DeltaNp63alpha, DeltaNp63beta, and DeltaNp63 gamma) in the mouse ovary. Reverse transcription-polymerase chain reaction experiments with primers specific for different p63 isoforms demonstrated that transcripts encoding the transactivation domain and alpha isoforms were preferentially expressed in the ovary. Immunolocalization of p63 proteins, presumably that of full-length p63alpha isoform, was observed in the oocytes of primordial, primary, and two-layered secondary follicles. However, positive staining was not detected in the oocytes of multi-layered secondary follicles and antral follicles as they continued to develop. This data suggests that p63 may be implicated in the meiosis and cell cycle control of germ cells in the mouse ovary. | ||||
| Ovarian localization | Primordial Germ Cell, Oocyte, Granulosa, Luteal cells | ||||
| Comment | Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Gonfloni S et al. Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl-TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments. p63 protects the female germ line during meiotic arrest. Suh EK et al. Meiosis in the female germ line of mammals is distinguished by a prolonged arrest in prophase of meiosis I between homologous chromosome recombination and ovulation. How DNA damage is detected in these arrested oocytes is poorly understood, but it is variably thought to involve p53, a central tumour suppressor in mammals. While the function of p53 in monitoring the genome of somatic cells is clear, a consensus for the importance of p53 for germ line integrity has yet to emerge. Here we show that the p53 homologue p63 (refs 5, 6), and specifically the TAp63 isoform, is constitutively expressed in female germ cells during meiotic arrest and is essential in a process of DNA damage-induced oocyte death not involving p53. We also show that DNA damage induces both the phosphorylation of p63 and its binding to p53 cognate DNA sites and that these events are linked to oocyte death. Our data support a model whereby p63 is the primordial member of the p53 family and acts in a conserved process of monitoring the integrity of the female germ line, whereas the functions of p53 are restricted to vertebrate somatic cells for tumour suppression. These findings have implications for understanding female germ line fidelity, the regulation of fertility and the evolution of tumour suppressor mechanisms. | ||||
| Follicle stages | Preovulatory, Corpus luteum | ||||
| Comment | Differential expression of p63 isoforms in female reproductive organs Kurita T, et al . p63 is the identity switch for uterine/vaginal epithelial cell fate, and disruption of p63 expression by diethylstilbestrol (DES) induces cervical/vaginal adenosis in mice. In this article, we report the expression patterns of p63 isoforms (TA, DeltaN, alpha, beta and gamma) in mice, focusing on the reproductive tract. We also present the reproductive tract phenotype of female p63(-/-) mice. Finally, to better evaluate the potential role of p63 in human development of DES-induced cervical/vaginal adenosis, we describe the ontogeny of p63 in human female fetuses. In adult mice, the DeltaN isoforms of p63 were expressed only in squamous/basal/myoepithelial cells of epithelial tissues, while TA isoforms of p63 were highly expressed in germ cells of the ovary and testis. In fetal mice, the DeltaN and alpha forms of p63 were expressed in the cloacal and urogenital sinus epithelia. In the female p63(-/-) mice, the sinus vagina developed, but p63(-/-) sinus vaginal epithelium failed to undergo squamous differentiation confirming an essential role of p63 in squamous epithelial differentiation. Although TAp63 was highly expressed in developing primordial germ cells/oocytes, p63(-/-) ovaries and oocytes developed normally. The ontogeny of p63 in female reproductive organs was essentially identical in mouse and human. In the human fetus at the susceptible stage for DES-induced cervical/vaginal adenosis, most cervical/vaginal epithelial cells were columnar and negative for p63. Therefore, inhibition of p63 expression by DES should change the cell fate of human Mullerian duct epithelial cells and cause cervical/vaginal adenosis as previously demonstrated in mouse. | ||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
5 mutations
Species: mouse
Species: mouse
Species: mouse
Species: human
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | June 25, 2003, 12:55 p.m. | by: |
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| last update: | Jan. 20, 2021, 12:24 a.m. | by: | hsueh email: |
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