p73 belongs to a small but important family of p53-related proteins (p53, p63, p73). These proteins, which are encoded by the Trp53, Trp63, and Trp73 genes, respectively, are all transcription factors involved in the regulation of development, cell death, proliferation, stem cell renewal, and cell fate commitment, as well as tumorigenesis (Yang et al. 2002; Vousden and Lane 2007). Like p53, several different protein isoforms of p63 and p73 have been reported, whose functions may compete with, synergize with, or be unrelated to those of p53.
The Trp73 gene, discovered in 1997 (Kaghad et al. 1997), contains two promoters that drive the expression of two major groups of p73 isoforms with opposing cellular actions: The TAp73 isoforms contain the p73 transactivation domain (TA) and exhibit proapoptotic activities (M?et al. 2005; Wang et al. 2007), whereas the ΔNp73 isoforms lacking the N-terminal TA domain are anti-apoptotic (Grob et al. 2001).
NCBI Summary:
This gene encodes a member of the p53 family of transcription factors involved in cellular responses to stress and development. It maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and thought to contain multiple tumor suppressor genes. The demonstration that this gene is monoallelically expressed (likely from the maternal allele), supports the notion that it is a candidate gene for neuroblastoma. Many transcript variants resulting from alternative splicing and/or use of alternate promoters have been found for this gene, but the biological validity and the full-length nature of some variants have not been determined. [provided by RefSeq, Feb 2011]
General function
Tumor suppressor, DNA binding, Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Follicle development, Early embryo development
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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. The Trp73 gene, discovered in 1997 (Kaghad et al. 1997), contains two promoters that drive the expression of two major groups of p73 isoforms with opposing cellular actions: The TAp73 isoforms contain the p73 transactivation domain (TA) and exhibit proapoptotic activities (M?et al. 2005; Wang et al. 2007), whereas the ΔNp73 isoforms lacking the N-terminal TA domain are anti-apoptotic (Grob et al. 2001).
Expression regulated by
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Ovarian localization
Oocyte
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Pan et al cloned the p73 cDNA from zebrafish ovary RNA. The consensus open reading frame (1923bp) encodes a polypeptide of 640 amino acids which shares 70-95% identity to the p73 of other vertebrates. Expression of zebrafish p73 mRNA is restricted to tissues such as skin, fin, brain, ovary, and testis, in contrast to the ubiquitous expression of zebrafish p53 and p63. During embryonic development, p73 transcripts are detected from the zygote period to the early larva stage. Whole-mount in situ hybridization reveals that p73 expression is in the brain, including olfactory bulbs, telencephalon, and hypothalamus, as well as in the pharyngeal arches and the nose. Moreover, p73 protein is found in the ovary and testis sections by immunohistochemical staining.
Follicle stages
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Tomasini R et al. The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and DeltaNp73, with opposing pro- and anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles of p73 isoforms in cellular events such as tumor initiation, embryonic development, and cell death remain unclear. To determine which aspects of p73 function are attributable to the TAp73 isoforms, we generated and characterized mice in which exons encoding the TAp73 isoforms were specifically deleted to create a TAp73-deficient (TAp73(-/-)) mouse. Here we show that mice specifically lacking in TAp73 isoforms develop a phenotype intermediate between the phenotypes of Trp73(-/-) and Trp53(-/-) mice with respect to incidence of spontaneous and carcinogen-induced tumors, infertility, and aging, as well as hippocampal dysgenesis. In addition, cells from TAp73(-/-) mice exhibit genomic instability associated with enhanced aneuploidy, which may account for the increased incidence of spontaneous tumors observed in these mutants. Hence, TAp73 isoforms exert tumor-suppressive functions and indicate an emerging role for Trp73 in the maintenance of genomic stability.
TAp73−/− mice mate normally and the females display normal cyclicity (Supplemental Fig. S3B; data not shown). To investigate the nature of TAp73−/− female infertility, we induced superovulation in 3- to 4-wk-old TAp73−/− females and their wild-type littermate sisters using exogenous gonadotropins. In contrast to wild-type females, no oocytes were present in the fallopian tubes of TAp73−/− females 16 h after administration of hCG. When the ovaries and oviducts of TAp73−/− females were dissected, we found that the ovulated oocytes were trapped under the bursa and did not progress toward the fallopian tubes (Fig. 2A, right). Upon collection of these oocytes, it became clear that TAp73−/− females also ovulated fewer gametes (Fig. 2B).Although significant differences were observed in the number of quiescent (primordial) or early growing (primary) follicles, numbers of early secondary follicles were comparable (Fig. 2C). The majority of embryos obtained from TAp73−/− oocytes arrested during early cleavage, resulting in embryos with multinucleated blastomeres, and blastocysts of inferior quality with an abnormal cell number (Fig. 3E,F). Thus, Trp73 is a maternal-lethal effect gene, because a lack of TAp73 in developing oocytes leads to a failure of preimplantation embryonic development.