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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of proteins have been identified whose expression or activity is regulated by cell growth. We have produced a monoclonal antibody against a new cell-growth regulated protein found in normal human fibroblasts. We have shown that this antibody recognizes a 51/52-kDa doublet (p51/52) found mainly in normal cells. This doublet is sensitive to degradation by the calcium-activated protease, calpain, breaking down to a 37/38-kDa doublet. The relative amount of the two members of the 51/52-kDa doublet changes when serum-starved cells reenter the cell cycle. Quiescent cells express mainly the 51-kDa form; the 52-kDa form becomes more abundant upon refeeding serum-starved cells. Transformed cells express either very small amounts of this doublet, and then predominantly the 52-kDa form, or no detectable amount of either form. These characteristics distinguish this molecule from several other known growth-regulated proteins such as statin and the anti-oncogene p53.
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PMID:Characterization of p51/52, a cell-growth regulated protein of WI-38 cells. 170 23

The p53 tumor suppressor orchestrates a number of important genes involved in cell-cycle control and apoptosis. Mice deficient for p53 show a high incidence of cancer but are developmentally normal suggesting that compensatory mechanisms exist in embryogenesis and differentiation. The new KET protein is the first mammalian protein with strong homology to p53 in all evolutionary conserved regions. This conservation makes a functional redundancy of the two proteins in cell-cycle control possible. KET is expressed during embryonic development and in certain adult tissues. Among all of the known p53 proteins of different species KET is most closely related to that found in squid. The relationship between KET and the invertebrate p53 protein sheds light on the evolutionary origin of p53. KET appears to be an ancestral p53-related protein in vertebrates with a possible role in development and differentiation while the ubiquitously expressed p53 protein attained its general role as 'guardian of the genome' during evolution.
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PMID:A novel protein with strong homology to the tumor suppressor p53. 931 5

The p53 tumor suppressor gene, which is induced by DNA damage and/or stress stimuli, causes cells to undergo G1-arrest or apoptotic death; thus it plays an essential role in human carcinogenesis. We have searched for p53-related genes by using degenerate PCR, and have identified two cDNA fragments similar to but distinct from p53: one previously reported, p73, and the other new. We cloned two major splicing variants of the latter gene and named these p51A and p51B (a human homologue of rat Ket). The p51A gene encodes a 448-amino-acid protein with a molecular weight of 50.9 kDa; and p51B, a 641-amino-acid protein with a molecular weight of 71.9 kDa. In contrast with the ubiquitous expression of p53, expression of p51 mRNA was found in a limited number of tissues, including skeletal muscle, placenta, mammary gland, prostate, trachea, thymus, salivary gland, uterus, heart and lung. In p53-deficient cells, p51A induced growth-suppression and apoptosis, and upregulated p21waf-1 through p53 regulatory elements. Mutations in p51 were found in some human epidermal tumors.
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PMID:Cloning and functional analysis of human p51, which structurally and functionally resembles p53. 966 64

The p53 pathway provides a physiological system for integrating signals from diverse insults and eliciting adaptive cellular responses that include (but importantly are not restricted to) growth arrest and apoptosis. Defects in the pathway are prevalent in cancer, most notably being associated with mis-sense mutations in p53 itself. This leads to the inability of p53 to act as a transcription factor and thus to the non-occurrence of downstream events. Recent data indicate that the stability (and hence level) of p53 protein in cells is regulated by its interaction with mdm2: this results in enhanced p53 degradation by ubiquitin-mediated events. Since mdm2 is itself regulated by p53, loss of function of p53 leads to lack of mdm2 and thus to p53 protein accumulation. This provides a mechanistic explanation for the observation that p53 accumulation is associated with neoplasia. It may be that accumulation of p53 in the absence of p53 mutation can occur as a consequence of mdm2 defects, as well as being a physiological response in many situations. Another recent development is the recognition of p53 homologues (p73 alpha, p73 beta, and KET) which have many sequence and probable structural features in common with p53. It seems likely that this will reveal another layer of complexity in the control and regulation of p53 and its role in physiology and pathology.
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PMID:Why is p53 protein stabilized in neoplasia? Some answers but many more questions? 966 99

The p53 protein, which regulates the rate of cell division and death, is the most frequently mutated tumor suppressor to be identified so far in human cancers. Recently, a gene with significant homology to p53, termed p73, has been identified in a chromosomal region that is implicated in the molecular pathogenesis of neuroblastoma. We have cloned a second human p53-related gene, termed p73L, which shows strong amino-acid similarity to p73. The p73L gene is mapped to human chromosome 3q27-28 using in situ hybridization technique. p73L encodes a protein of 586 amino acids and its putative DNA binding domain (DBD) has high identities to those of p53 (60.6%) and to p73 (87.8%). Northern blot analysis, which demonstrated that the expression profiles of p73L and p73 mRNAs are distinct in some tissues, implies that p73 and p73L may have separate, distinct roles in different tissues.
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PMID:A second p53-related protein, p73L, with high homology to p73. 970 73

KET is a member of the newly discovered family of proteins that is related to the tumor suppressor p53. Here we describe the molecular cloning of a human cDNA of 4846 bp encoding a protein of 680 amino acids. The human KET protein shares 98% identity with the previously characterized rat homolog. The remarkably high degree of conservation lends support to the notion that KET proteins have important basic functions in development and differentiation. Using the GeneBridge 4 radiation hybrid panel, we have mapped KET to human Chromosome (Chr) 3q27. KET is located between the somatostatin gene SST (proximal) and the apolipoprotein D gene APOD (distal) in a region of conserved synteny to mouse Chr 16. This chromosomal region is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the hitherto unidentified Loh2 gene, a putative suppressor of angiogenesis. The murine homolog Ket was mapped in an interspecific backcross panel and falls into this region of loss of heterozygosity. From our mapping data we infer that KET might act as a tumor suppressor and is considered as a candidate for Loh2.
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PMID:Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16. 979 41

We have measured the stability and stoichiometry of variants of the human p53 tetramerization domain to assess the effects of mutation on homo- and hetero-oligomerization. The residues chosen for mutation were those in the hydrophobic core that we had previously found to be critical for its stability but are not conserved in human p73 or p51 or in p53-related proteins from invertebrates or vertebrates. The mutations introduced were either single natural mutations or combinations of mutations present in p53-like proteins from different species. Most of the mutations were substantially destabilizing when introduced singly. The introduction of multiple mutations led to two opposite effects: some combinations of mutations that have occurred during the evolution of the hydrophobic core of the domain in p53-like proteins had additive destabilizing effects, whereas other naturally occurring combinations of mutations had little or no net effect on the stability, there being mutually compensating effects of up to 9.5 kcal/mol of tetramer. The triple mutant L332V/F341L/L344I, whose hydrophobic core represents that of the chicken p53 domain, was nearly as stable as the human domain but had impaired hetero-oligomerization with it. Thus, engineering of a functional p53 variant with a reduced capacity to hetero-oligomerize with wild-type human p53 can be achieved without any impairment in the stability and subunit affinity of the engineered homo-oligomer.
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PMID:Mutually compensatory mutations during evolution of the tetramerization domain of tumor suppressor p53 lead to impaired hetero-oligomerization. 1009 82

Perturbation of p53 protein function is a common, if not universal, finding in human cancer. Tumor suppression by p53 is due, at least in part, to its ability to activate transcription of certain genes involved in cell cycle control and apoptosis (programmed cell death). Two additional members of the mammalian p53 family, p73 and p51, which is also known as p40, p63, KET, or p73L, were recently identified. Both of these proteins share substantial sequence homology with p53 and can, at least when overproduced, activate p53-responsive promoters and induce apoptosis. Nonetheless, data on differences between these proteins and p53 are emerging. For example, p73 is not induced by DNA damage and is not targeted for inactivation by viral oncoproteins such as simian virus 40 (SV40) T antigen, adenovirus E1B 55K, and human papillomavirus E6. In contrast to p53, neither p73 nor p51 appears to be frequently mutated in human cancers on the basis of the limited studies reported to date. Finally, unlike p53, cells produce multiple p73 and p51 isoforms as a result of alternative splicing, and production of p73 and p51 appears to be restricted to certain tissues. Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis.
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PMID:The emerging p53 gene family. 1020 77

The role that the p53 tumor suppressor gene product plays in cellular differentiation remains controversial. However, recent evidence indicates that p53 is required for proper embryogenesis. We have studied the effect of p53 on the expression mediated by the promoter of the rat muscle-specific phosphoglycerate mutase gene (M-PGAM), a marker for cardiac and skeletal muscle differentiation. Experiments involving transient transfection, mobility shift assay, and site-directed mutagenesis demonstrated that p53 specifically binds and transactivates the M-PGAM promoter. The p53-related proteins p51A and p73L also transactivated M-PGAM. Moreover, stable expression of a p53 dominant mutant in C2C12 cells blocked the induction of M-PGAM expression during the myoblast to myotube transition and the ability of p53, p51A, and p73L to transactivate the M-PGAM promoter. In addition, impaired expression of M-PGAM was observed in a subset of p53-null animals in heart and muscle tissues of anterior-ventral location. These results demonstrate that p53 is a transcriptional activator of M-PGAM that contributes in vivo to the control of its cardiac expression. These data support previous findings indicating a role for p53 in cellular differentiation.
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PMID:p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. 1035 11

p51/p63 is a novel p53 homologue that has been shown to act as a transcriptional activator through the p53-binding sequence of the p21/WAF1 promoter and to induce apoptosis when it is expressed transiently in a human tumor cell line. We developed transcription assay systems for these two related genes in both Saccharomyces cerevisiae and mammalian cells and used them to investigate the functional similarities and differences of these genes. We found that p51/p63 trans-activated the previously identified p53 target genes, but the degree of the transactivation by p51/p63 differed from that by p53. These results suggest that the cellular signal on p51/p63 cross-talks partially but not completely with that of the p53 pathway.
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PMID:The transcriptional activities of p53 and its homologue p51/p63: similarities and differences. 1038 30


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