Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We and others recently isolated a human p53 homologue (p40/p51/p63/p73L) and localized the gene to the distal long arm of chromosome 3. Here we sought to examine the role of p40/p73L, two variants lacking the N-terminal transactivation domain, in cancer. Fluorescent in situ hybridization (FISH) analysis revealed frequent amplification of this gene locus in primary squamous cell carcinoma of the lung and head and neck cancer cell lines. (We named this locus AIS for amplified in squamous cell carcinoma.) Furthermore, amplification of the AIS locus was accompanied by RNA and protein overexpression of a variant p68(AIS) lacking the terminal transactivation domain. Protein overexpression in primary lung tumors was limited to squamous cell carcinoma and tumors known to harbor a high frequency of p53 mutations. Overexpression of p40(AIS) in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. Our results support the idea that AIS plays an oncogenic role in human cancer.
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PMID:AIS is an oncogene amplified in squamous cell carcinoma. 1080 2

The p53-related p73 and p63 genes encode proteins that share considerable structural and functional homology with p53. Despite similarities, their deletion in mice has different outcomes, implying that the three genes may play distinct roles in vivo. Here we show that endogenous p73 levels increase in neuroblastoma cells induced to differentiate by retinoic acid and that exogenously expressed p73, but not p53, is sufficient to induce both morphological (neurite outgrowth) and biochemical (expression of neurofilaments and neural cell adhesion molecule (N-CAM); down-regulation of N-MYC and up-regulation of pRB) markers of neuronal differentiation. This activity is shared, to different extents, by all p73 isoforms, whereas the transcriptionally inactive mutants of p73 isoforms are ineffective. Conversely, blockage of endogenous p73 isoforms with a dominant negative p73 results in the abrogation of retinoid-induced N-CAM promoter-driven transcription. Our results indicate that the p73 isoforms activate a pathway that is not shared by p53 and that is required for neuroblastoma cell differentiation in vitro.
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PMID:Induction of neuronal differentiation by p73 in a neuroblastoma cell line. 1080 58

Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.
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PMID:Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. 1083 77

p51A, or TAp63gamma, a translation product of gene p51, or p63, was identified as a homolog of p53 in its primary structure and transactivating function. p53 plays a decision-making role in inducing either cell cycle arrest or apoptosis in response to DNA damage, and thereby preserves genome integrity of living cells. To compare the biological activities between p51A and p53, cell lines with low-level, constitutive expression of each protein were obtained by cDNA transfection of mouse erythroleukemic cells. Production of p51A with an apparent molecular mass of 57-kilodalton (kD) accompanied induction of p21waf1 and appearance of hemoglobin-producing cells. After DNA-damaging treatment either with ultraviolet light (UV) irradiation or with actinomycin D, the p51A protein accumulated in time courses corresponding to those of wild-type p53, and caused an increase in the hemoglobin-positive cell count. In contrast, p53-accumulated cells underwent apoptosis without exhibiting the feature of erythroid differentiation. The mode of p21waf1 and Bax-alpha upregulations varied between p51A- and p53-expressing cells and between the types of DNA damage. These results suggest the possibility that p51A induces differentiation under genotoxic circumstances. There may be cellular factors that control p51A protein stability and transactivating ability.
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PMID:p51A (TAp63gamma), a p53 homolog, accumulates in response to DNA damage for cell regulation. 1087 67

p53 and its two homologues, p73 and p63, share considerable structural similarities, an ability to interact between themselves and to transactivate the same promoters, including for example p21. Furthermore, p73 can induce cell death via its interaction with c-Abl. In contrast, p63 has been demonstrated to be essential for limb and skin formation. We evaluated the expression of p63 and p73 in differentiating human keratinocytes in vitro. Skin biopsy and primary cultures of normal human epidermal keratinocytes (NHEK) express both p73 and p63. NHEK induced to differentiate in vitro by high calcium exposure show induction of p73 delta and downregulation of all isoforms of p63. This latter gene is predominantly expressed in its transcriptionally inactive form, DeltaNp63. We further evaluated the effect of either p73s or p63 transfected in either NHEK or transformed human keratinocytes (HaCat cells). p73 gamma, delta, and p63 were able to transactivate the promoters of loricrin and involucrin in both NHEK and HaCat cells. These results suggest the involvement of both p73 and p63 genes in keratinocyte terminal differentiation.
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PMID:p63 and p73 transactivate differentiation gene promoters in human keratinocytes. 1087 8

p53 plays an essential pro-apoptotic role, a function thought to be shared with its family members p73 and p63. Here, we show that p73 is primarily present in developing neurons as a truncated isoform whose levels are dramatically decreased when sympathetic neurons apoptose after nerve growth factor (NGF) withdrawal. Increased expression of truncated p73 rescues these neurons from apoptosis induced by NGF withdrawal or p53 overexpression. In p73-/- mice, all isoforms of p73 are deleted and the apoptosis of developing sympathetic neurons is greatly enhanced. Thus, truncated p73 is an essential anti-apoptotic protein in neurons, serving to counteract the pro-apoptotic function of p53.
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PMID:An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. 1091 51

The p53 homologue p63 is essential for ectodermal differentiation, such that p63-/- mice lack all squamous epithelia and teeth. The p63 gene expresses at least 6 different transcripts, but information regarding the expression, regulation and function of the different isoforms has remained sparse, due to the lack of adequate reagents directed specifically against the individual proteins. Here we characterize the expression of p63 alpha/delta Np63 alpha in benign and malignant lesions of the oral epithelium, using a specific antibody raised against a peptide derived from the C-terminus of p63 alpha, which does not cross-react with p53 or the other p53 homologue, p73. By immunohistochemical analysis, we show that these p63 isoforms are expressed in the nucleus of many cells. In normal and benign lesions, p63 alpha/delta Np63 alpha-expressing cells are mainly found suprabasally, whereas p53-expressing cells are restricted to the basal-cell layer. By RT-PCR, we show that delta Np63 alpha is the predominant isoform in cell lines from squamous-cell carcinomas of the head and neck, confirming our immunochemical observations. Our data are consistent with studies suggesting a role for p63 in the transit-amplifying population of epidermal cells. Over-expression of p63 alpha, and in particular the delta N form, was frequently seen in carcinomas. Taken together with previous analyses of p63 expression, our data suggest distinct roles for different p63 isoforms in the regulation of growth and/or differentiation of epithelial cells. Moreover, our data are compatible with the notion that p63 can act to promote neoplastic growth in the oral epithelium.
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PMID:Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions. 1089 41

p63, a recently identified member of the p53 gene family, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. To explore the penetrance of p63 in bladder carcinogenesis, we performed expression and mutation analyses of two major isotypes, TAp63 and deltaNp63, in 63 bladder specimens. In 12 normal tissues, TAp63 was expressed at an easily detectable level whereas deltaNp63 was absent or extremely low. While none of 47 carcinomas showed allelic deletion of the gene, marked reduction of TAp63 and abnormal overexpression of deltaNp63 were found in 25 (53.2%) and 30 (63.8%) carcinomas, respectively. Tumor-specific alteration of TAp63 and deltaNp63 expression was identified in two and three of six matched sets, respectively. In addition, reduced expression of TAp63 showed a correlation with tumor stage and grade. Abnormal expression of TAp63 or deltaNp63 isoform was also observed in three of four cell lines, and treatment with 5-Aza-2'-deoxycytidine led to up- or down-regulation of TAp63 and/or deltaNp63 expression, suggesting that the promoters of both isoforms might be affected by DNA methylation, but not in a reciprocal fashion. No sequence alteration of p63 was identified in 47 carcinomas whereas 17 (34.8%) of these showed p53 mutations, and no association between p63 expression and the mutational status of p53 or expression of p21Waf1, MDM2, and 14-3-3sigma was recognized. Our data suggest that altered expression of p63 is a frequent event in bladder carcinogenesis and might contribute to the progression of bladder tumors, possibly via the mechanism(s) distinct from the p53 pathway.
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PMID:Frequent alteration of p63 expression in human primary bladder carcinomas. 1091 40

It has been assumed that the new members of the p53 protein family, p63 and p73, would have the same job as p53, namely, forcing cells to die if they or their DNA is damaged. Now, as Morrison and Kinoshita explain in their Perspective, one particular form of p73 has been found to be a survival factor rather than a death factor for sympathetic neurons during development (Pozniak et al.).
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PMID:Development. p73--guilt by association? 1089 79

Undifferentiated nasopharyngeal carcinoma (NPC) is an epithelial malignancy that is consistently associated with Epstein-Barr virus (EBV) but which very rarely has p53 gene mutations in primary tumours. Since the tumour suppressor p53 is mutated in most human cancers or the wild type protein is inactivated in a significant number of the remainder, here we have investigated cellular factors that could compromise p53 function in primary NPC. Twenty-five primary tumours were judged to carry only wild type p53 by SSCP analysis of all exons and sequence determination of exons 4-9. Only one tumour was found to express significant levels of hMdm2 and in 24/25 there were no detectable mutations or deletions in exons 1beta and 2 of the p14(ARF) gene. However, immunohistochemistry consistently revealed that all the tumour cells express substantial amounts of the p53-related protein p63. Semi-quantitative RT-PCR analysis of mRNA from tumour biopsies showed that the dominant species expressed was invariably the truncated deltaN-isotype. Since this can block p53-mediated transactivation, it is potentially a dominant-negative isoform. In normal nasopharyngeal epithelium the distribution of p63 was restricted to the proliferating basal and suprabasal layers. We suggest that deltaN-p63 is a good candidate as a suppressor of wild type p53 function in these tumours and also that it may prove to be a valuable diagnostic marker for undifferentiated NPC.
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PMID:High level expression of deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? 1091 1


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