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)

Dominant-negative and/or loss-of-function mutations of the p53 tumor suppressor gene are frequently found in squamous cell carcinomas of the skin and of the head-and-neck region. In order to identify the precise mechanisms of inactivation of p53 in tumors of this class, we examined the status of p53 RNA, protein and DNA in a panel of eight human squamous carcinoma cell lines (head-and-neck, 3; esophagus, 1; lung, 1; uterine cervix, 2; vulva, 1). Three lines (A253, CaLu-1, SqCC/Y1) failed to express any p53 mRNA. A253 cells contained a single p53 allele without mutations in exons 2-9, suggesting that the lack of transcription was the result of mutations in the regulatory region of the gene. Both p53 alleles were deleted in CaLu-1 cells, whereas the single allele present in SqCC/Y1 cells was rearranged and carried two missense mutations in exon 5. Two cell lines (A431, FaDu) expressed only 50% of the normal level of p53 mRNA, either because only one allele was present (A431), or because only one of the two alleles was transcribed (FaDu). The two cervical carcinoma lines (CaSki, C4-1) expressed normal levels of p53 mRNA, but no wild type protein, presumably as a result of accelerated degradation by the human papillomavirus 16 or -18 E6 oncoprotein present in these cells as previously described (Scheffner et al., Proc. Natl. Acad. Sci. USA 88:5523-5527; 1991). Three of the lines expressed only mutant p53 protein (A431, FaDu, CE-48) resulting from missense mutations in codons 248 and 273.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines. 148 18

The cellular p53 protein is so called because of its molecular weight as determined by SDS-polyacrylamide gel electrophoresis. It was originally classified as a nuclear oncogene product when it was shown by DNA transfection experiments that p53 is able to extend the lifespan of primary rodent cell cultures and to cooperate with an activated ras oncogene to achieve complete transformation of primary cells. However, there is now conclusive evidence that loss of normal p53 expression may be an important step in cell transformation and tumorigenesis. Furthermore, it has been shown that mutant p53 was used for the experiments demonstrating the immortalizing and transforming capacity of p53. Wild-type p53 seems to negatively regulate cell growth and division. So far, the basic function of p53 is not known. Biochemical variability seems to be a key feature of p53 and an understanding of biochemical variations in the p53 protein may contribute to an understanding of how p53 is regulated or how p53 may regulate cell proliferation. Thus, the present review will focus on the biochemical properties of p53.
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PMID:Biochemical properties of the growth suppressor/oncoprotein p53. 150 81

Human breast carcinoma MCF-7 cells seeded on type I collagen-coated dishes were provided with an anchor via the collagen receptor, integrin, and grew as actively as those in plastic tissue culture dishes. In contrast, cells seeded on a layer of soft agar became anchorage-deficient and their growth was significantly inhibited, although the cell viability and the cell cycle distribution were unaffected. Immunoprecipitation analysis revealed that mutant p53 was phosphorylated at tyrosine in the anchorage-provided cells. In contrast, the p53 in the anchorage-deficient cells was present in 2-fold greater amount, but was phosphorylated to a lesser extent. Addition of a potent protein-tyrosine kinase inhibitor, herbimycin A, to the anchorage-provided cells caused an elevated level of p53, and inhibitions of cell proliferation and p53 phosphorylation, without interfering with the cell adhesion to the substratum. These results demonstrated that the growth inhibition by anchorage-deficiency or by herbimycin A is associated with an elevated p53 level and reduced p53 phosphorylation at tyrosine.
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PMID:Growth inhibition by anchorage-deficiency is associated with increased level but reduced phosphorylation of mutant p53. 150 70

Somatic mutations of the p53 gene have been implicated as causal events in the formation of a large number of common human tumors. Several lines of evidence suggest that the nuclear phosphoprotein encoded for by the wild-type gene (wt-p53) plays a role in regulating cell proliferation. Wt-p53 protein encodes a potent negative growth regulatory function that is lacking in mutant forms of the protein found in human tumors. In this review, the relationship between the expression of wt-p53 protein and cell proliferation is examined with emphasis on recent studies that provide clues as to the possible role that p53 plays in cell cycle regulation. A model for the action of p53 in regulating cell proliferation is proposed in which wt-p53 acts as a "checkpoint" protein to control the transit of cells through the restriction point in late G1-phase. After cells pass this "checkpoint" they become committed to enter S-phase and initiate DNA replication. This checkpoint function may be defective in cells that lack p53, express mutant p53, or in which the antiproliferative form of the protein is functionally inactive. Under these conditions stringent control of the initiation of DNA replication may no longer be possible, providing an environment conducive to the emergence oncogenic clones.
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PMID:Cell cycle regulation and the p53 tumor suppressor protein. 151 Nov 88

Loss of cell cycle control and acquisition of chromosomal rearrangements such as gene amplification often occur during tumor progression, suggesting that they may be correlated. We show here that the wild-type p53 allele is lost when fibroblasts from patients with the Li-Fraumeni syndrome (LFS) are passaged in vitro. Normal and LFS cells containing wild-type p53 arrested in G1 when challenged with the uridine biosynthesis inhibitor PALA and did not undergo PALA-selected gene amplification. The converse occurred in cells lacking wild-type p53 expression. Expression of wild-type p53 in transformants of immortal and tumor cells containing mutant p53 alleles restored G1 control and reduced the frequency of gene amplification to undetectable levels. These studies reveal that p53 contributes to a metabolically regulated G1 check-point, and they provide a model for understanding how abnormal cell cycle progression leads to the genetic rearrangements involved in tumor progression.
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PMID:Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. 152 30

The transformation-related cellular phosphoprotein p53 interacts with a variety of viral and cellular proteins and with itself to form high molecular weight complexes. The formation of high molecular weight complexes correlates with the transformed morphology of the cells whereas in non-transformed cells low molecular weight forms are predominant. Thus, aggregation seems to be involved in the regulation of biological functions of p53. Analyzing wild-type and mutant p53 in the same cellular environment i.e. after an in vitro transcription/translation reaction in rabbit reticulocytes we found high molecular weight forms for wild-type and mutant p53. The sedimentation profile resembled the profile obtained for mutant p53 from transformed cells. As shown by dilution experiments, aggregation of p53 was not due to high p53 protein concentrations. Although p53 is known to bind RNA, treatment with RNAse did not change the aggregation state of p53 suggesting that RNA may not contribute to the quaternary structure of p53. High molecular weight aggregates of p53 were resistant to treatment with 1 M NaCl and also stable in weak acidic conditions. Alkaline pH as well as treatment with 3.5 M NaCl led to a disaggregation of high molecular weight complexes of p53. This treatment resulted in low molecular weight forms consisting probably of dimers to tetramers whereas monomers of p53 are hardly detectable. A nearly complete disaggregation was obtained only with the ionic denaturing detergent sodium dodecyl sulfate. Therefore, one has to assume different types of protein-protein interactions leading to the various quaternary structures of p53.
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PMID:Protein-protein interactions in high molecular weight forms of the transformation-related phosphoprotein p53. 154 Jun 29

Human wild-type and mutant p53 genes were expressed under the control of a galactose-inducible promoter in Saccharomyces cerevisiae. The growth rate of the yeast was reduced in cells expressing wild-type p53, whereas cells transformed with mutant p53 genes derived from human tumors were less affected. Coexpression of the normal p53 protein with the human cell cycle-regulated protein kinase CDC2Hs resulted in much more pronounced growth inhibition that for p53 alone. Cells expressing p53 and CDC2Hs were partially arrested in G1, as determined by morphological analysis and flow cytometry. p53 was phosphorylated when expressed in the yeast, but differences in phosphorylation did not explain the growth inhibition attributable to coexpression of p53 and CDC2Hs. These results suggest that wild-type p53 has a growth-inhibitory activity in S. cerevisiae similar to that observed in mammalian cells and suggests that this yeast may provide a useful model for defining the pathways through which p53 acts.
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PMID:Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae. 154 17

Previous studies by others using metabolic labeling, cell lysis, and immunoprecipitation have reported elevated levels of p53 protein in blast cells derived from patients with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML), whereas p53 protein was not detected in normal light-density bone marrow cells. In this report, using the same detection methods, we confirm the negligible expression of p53 protein in normal light density marrow cells. However, we find clearly significant levels of p53 protein expression in enriched normal human marrow blast populations. Furthermore, using a panel of p53 specific monoclonal antibodies, we find the p53 protein constitutively synthesized by normal marrow blasts has the immunologic phenotype identified by PAb240 that reportedly recognizes a common conformational-dependent epitope on mutant p53. We have also found that the p53 immunologic subclass identified by PAb240 exists in normal human circulating lymphocytes either resting, serum starved, or PHA activated. In summary, it is clear that (1) normal marrow blast populations provide the appropriate control for assessing the levels of p53 protein expression in leukemic blast cells; and (2) PAb240 cannot be used to distinguish p53 mutated at the DNA level from normal p53 in fresh human hematopoietic cells.
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PMID:Constitutive expression of p53 protein in enriched normal human marrow blast cell populations. 138 7

Epidermolysis bullosa, a rare genodermatosis, is characterized by increased skin fragility manifest as blistering and sometimes accompanied by scarring. The latter is particularly severe in the recessive dystrophic variant and may be complicated by the development of squamous carcinoma in up to 30% of patients. We have studied 23 such tumours in six patients with this variant, with an anti-serum to p53 protein. Twenty-six per cent of the squamous carcinomas labelled positively for mutant-type p53 protein. This low figure, however, reflects the large number of well-differentiated tumours in this series, where 14 out of 15 were negative. In the moderate to poorly differentiated examples the positivity rate was 63%. Of the three patients in the latter category, one has died from disseminated tumour and another has widespread metastases. The findings support the hypothesis that mutant p53 protein expression correlates with poorer tumour differentiation. They also suggest a possible correlation between p53 protein expression and tumour behaviour.
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PMID:Expression of mutant p53 gene in squamous carcinoma arising in patients with recessive dystrophic epidermolysis bullosa. 156 10

Products of a number of mutant p53 genes bind with high affinity to members of the hsp70 family of chaperonin proteins, whereas wild type p53 lacks this type of association. Examination of the sequences of p53 genes from five different species enabled us to predict domains on p53 which may be involved in the association with hsp70 family members. A synthetic polypeptide (Pro-17-Gly) corresponding to the candidate hsp70 binding domain bound to in vitro translated hsp70 as determined by affinity chromatography and nondenaturing gel mobility shift assays. In addition, the Pro-17-Gly peptide competitively inhibited association between hsp70 and p53, an activity which was determined by immunoprecipitation with anti-p53 monoclonal antibody PAb240. The data indicate that p53 contains a hsp70 binding domain, which is located in a highly conserved region at the amino terminus of the protein, and may participate in the cellular function of wild-type p53 or in the transforming capacity of p53 mutants.
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PMID:hsp70 binds specifically to a peptide derived from the highly conserved domain (I) region of p53. 156 24


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