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)

Skeletal muscle differentiation entails the coordination of muscle-specific gene expression and terminal withdrawal from the cell cycle. This cell cycle arrest in the G0 phase requires the retinoblastoma tumor suppressor protein (Rb). The function of Rb is negatively regulated by cyclin-dependent kinases (Cdks), which are controlled by Cdk inhibitors. Expression of MyoD, a skeletal muscle-specific transcriptional regulator, activated the expression of the Cdk inhibitor p21 during differentiation of murine myocytes and in nonmyogenic cells. MyoD-mediated induction of p21 did not require the tumor suppressor protein p53 and correlated with cell cycle withdrawal. Thus, MyoD may induce terminal cell cycle arrest during skeletal muscle differentiation by increasing the expression of p21.
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PMID:Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. 786 39

We have previously demonstrated that the gonadotropin-mediated inhibition of apoptosis in ovarian granulosa cells is linked to changes in the expression of several cell death-related genes, including members of the bcl-2 gene family (bcl-2, bax, and bcl-x). Recently, the product of the p53 tumor suppressor gene, a protein reported to play a critical role in regulating cell proliferation and death, has been shown to directly modulate the transcriptional activity of the bcl-2 and bax genes. In addition, the actions of p53 may be amplified through a cooperative interaction with another tumor suppressor protein, the product of the Wilms' tumor suppressor gene (WT-1). Based on our identification of a potential role for bcl-2-related factors in regulating granulosa cell apoptosis and the reported function of p53 as a regulator of bcl-2 and bax gene transcription in extragonadal cells, the present studies were conducted to determine whether the p53 and WT-1 genes are expressed and gonadotropin regulated in the rat ovary and to investigate whether granulosa cell apoptosis is linked to elevated levels of tumor suppressor gene expression. Northern blot analysis of total RNA prepared from immature (27-day-old) rat ovaries revealed the presence of a single p53 messenger RNA (mRNA) transcript (2.0 kilobases) and multiple WT-1 messages (1.8, 3.5, and 7.5 kilobases). Subcutaneous injection of immature rats with 10 IU equine CG (eCG) reduced the levels of p53 and WT-1 mRNA to 71 +/- 9% (P < 0.05) and 46 +/- 3% (P < 0.05), respectively, of saline-treated control levels after 2 days. The inhibition of tumor suppressor gene expression by eCG treatment was associated with a marked reduction in the number of apoptotic granulosa cells and atretic follicles. Furthermore, immunohistochemical analysis revealed that p53 protein was localized exclusively to nuclei of apoptotic granulosa cells of atretic follicles, and that p53 immunostaining was reduced to undetectable levels after in vivo treatment with eCG. To further evaluate whether granulosa cell apoptosis is linked to increased expression of tumor suppressor genes, we analyzed levels of p53 and WT-1 mRNA in antral follicles induced to undergo atresia in vitro by serum-free culture.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Expression of the p53 and Wilms' tumor suppressor genes in the rat ovary: gonadotropin repression in vivo and immunohistochemical localization of nuclear p53 protein to apoptotic granulosa cells of atretic follicles. 789 50

Seventy-five % of the world's oral cancers arise in developing countries. In high incidence areas of Southeast Asia such as Papua New Guinea (PNG) the major region-specific risk exposure is betel quid chewing. While it has been shown that p53 gene mutations in the conserved midregion (exons 5-9) are a common feature of oral cancers in the developed world, there is no information on this type of genetic lesion in betel quid-associated oral cancers. We examined 50 oral squamous cell carcinomas, 20 from Baltimore, MD and 30 from PNG, for mutations in exons 5-9 of the p53 gene. DNA extracted from frozen biopsies was amplified by polymerase chain reaction, the purified product was sequenced directly, and mutations were confirmed by repeating the entire procedure. Mutations were found in 3 of 30 tumors from PNG (10%), whereas 9 mutations were detected among the 20 tumors (45%) from Baltimore, MD. This difference in frequency is statistically significant (P < 0.01) by chi 2 analysis. Nuclear accumulation of p53 protein, determined by immunohistochemistry with the CM-1 antiserum, was observed in the PNG cases harboring a missense mutation of the p53 gene. In agreement with the low number of PNG cancers with mutations, only 17% of the cases from PNG were immunostain positive. To explore whether less conserved regions of the gene are preferential targets for alterations in this patient group, sequence analysis in tumors from PNG was extended to outlying regions of the gene (all of exons 4 and 10, and splice sites), but mutations in only two additional tumors were identified. The presence of human papillomavirus DNA in PNG cases was examined with a polymerase chain reaction-based procedure, and viral sequences (human papillomavirus strains 11/16) were detected in two tumors. Human papillomavirus-triggered degradation of the tumor suppressor protein is thus unlikely to be a typical pathway to p53 dysfunction in tumors from PNG.
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PMID:Mutations in the conserved regions of p53 are infrequent in betel-associated oral cancers from Papua New Guinea. 801 86

The p53 tumor suppressor protein, which is commonly mutated in human cancers, has been shown to interact directly with virally encoded from papillomavirus, adenovirus, and simian virus 40. The disruption of p53 function may be required for efficient replication of certain viruses and may also play a role in the development of virally induced malignancies. Infection with Epstein-Barr virus (EBV) has been associated with the development of B-cell lymphomas and nasopharyngeal carcinoma. Here we show that the EBV immediate-early protein, BZLF1 (Z), which is responsible for initiating the switch from latent to lytic infection, can interact directly in vitro and in vivo with the tumor suppressor protein, p53. This interaction requires the coiled-coil dimerization domain of the Z protein and the carboxy-terminal portion of p53. Overexpression of wild-type p53 inhibits the ability of Z to disrupt viral latency. Likewise, Z inhibits p53-dependent transactivation in lymphoid cells. The direct interaction between Z and p53 may play a role in regulating the switch from latent to lytic viral infection.
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PMID:Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency. 811 24

The tumor suppressor protein p53 was first isolated as a simian virus 40 large T antigen-associated protein and subsequently was found to function in cell proliferation control. Tumor-derived mutations in p53 occur predominantly in four evolutionarily conserved regions spanning approximately 50% of the polypeptide. Previously, three of these regions were identified as essential for T-antigen binding. We have examined the interaction between p53 and T antigen by using Escherichia coli-expressed human p53. By a combination of deletion analysis and antibody inhibition studies, a region of p53 that is both necessary and sufficient for binding to T antigen has been localized. This function is contained within residues 94 to 293, which include the four conserved regions affected by mutation in tumors. Residues 94 to 293 of p53 were expressed in both wild-type and mutant forms. T-antigen binding was unaffected by tumor-derived mutations which have been associated with the wild-type conformation of p53 but was greatly reduced by mutations which were previously shown to alter p53 conformation. Our results show that, like T-antigen binding to the Rb tumor suppressor protein, T antigen appears to interact with the domain of p53 that is commonly mutated in human tumors.
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PMID:Analysis of a protein-binding domain of p53. 838 47

Eight nonamer peptides that comply with the major anchor residue motifs (the combination of amino acid residues at positions 2 and 9), R - K and R - R, of HLA-B27 (B*2705)-binding peptides were synthesized and tested for their direct binding to HLA class I alpha chains by the HLA class I alpha chain refolding assay previously described. One was a known B27 (B*2705)-binding heat shock protein peptide, HSP89 alpha (201-209), and the other seven were derived from the sequence of wild-type P53, a human tumor suppressor protein. A total of 36 HLA class I allospecificities were tested. HSP89 alpha (201-209) and two P53 peptides, P53 (362-370) and P53 (378-386), all possessing the motif R - K, bound strongly to B27 (B*2705) alpha chains. A weak binding was seen for P53 (272-280) and P53 (334-342), both showing the motif R - R. Most of these B27-binding peptides were found to bind to A3 alpha chains as well. In addition, P53 (173-181) and P53 (334-342), both with the R - R motif, showed substantial binding with A31 alpha chains. All the peptides carrying the motif R - K also showed weak binding with A31 alpha chains. The remaining two peptides, P53 (201-209) and P53 (282-290), with the motif R - R, did not show significant binding with any of the alpha chains tested. This study demonstrates both the specificity of peptide binding to a given HLA allelic product and the occurrence of cross-peptide-binding between the allelic products of different HLA loci.
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PMID:HLA class I binding of synthetic nonamer peptides carrying major anchor residue motifs of HLA-B27 (B*2705)-binding peptides. 846 93

Regulation of apoptosis (programmed cell death) is critical for maintaining tissue homeostasis. Recent studies indicate a tight coupling between cellular proliferation and apoptosis as cell cycle regulators such as Cyclin D, E1A and E7 appear to influence both events. Each of these modulators is able to bind to and inhibit the function of the retinoblastoma tumor suppressor protein (RB). RB functions, in part, by binding to and inactivating E2F transcription factors, preventing expression of E2F-activated genes associated with G1/S cell-cycle progression. Loss of functional RB deregulates E2F activity and, depending on cell type and environmental factors, promotes tumorigenesis or apoptotic death. To determine the effect of RB on IFN-gamma induced apoptosis, we treated RB-defective carcinoma cell lines and their respective RB-constituted sister clones with IFN-gamma and examined the cells for alterations characteristic of apoptosis. We observed that RB-defective cells, but not the RB-reconstituted clones, decreased in size following IFN-gamma treatment. IFN-gamma treatment caused increased cell detachment in the RB-defective lines but did not affect adherence of the RB-reconstituted clones. Assays for DNA fragmentation revealed lower molecular weight DNA and the apoptosis-associated oligo-nucleosomal ladder following IFN-gamma treatment of the RB-defective cells while higher molecular weight DNA was present in the IFN-gamma treated, RB-reconstituted lines. IFN gamma-induced apoptosis in RB-defective cells was enhanced by serum stimulation, which is also characteristic of p53-dependent E2F-1-mediated apoptosis. However, IFN-gamma induced apoptosis in RB-defective lines does not require wild-type p53 suggesting that, upon IFN-gamma induction, deregulated E2F-mediated apoptosis can also proceed via p53-independent pathways.
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PMID:Retinoblastoma protein inhibits IFN-gamma induced apoptosis. 862 2

We previously showed that expression of the bovine papillomavirus (BPV) E2 gene results in a dramatic inhibition of the proliferation of several human cervical carcinoma cell lines, including HeLa cells which contain human papillomavirus (HPV) type 18 DNA. We have assessed the status of endogenous G1 cell cycle regulatory proteins, including the tumor suppressor proteins, p53 and p105Rb, in order to investigate growth regulatory pathways in HeLa cells following E2 expression. The p53 tumor suppressor protein is stabilized following the introduction of the E2 gene into HeLa cells. This results in the induction of the p53-responsive gene encoding the cyclin dependent kinase (cdk) inhibitor, p21/WAF1, complex formation between p21/WAF1 and cdk2 and reduction of in vitro cdk2/cyclin E kinase activity. The reduced cdk kinase activity is accompanied by the accumulation of the growth inhibitory hypophosphorylated form of the tumor suppressor protein, p105Rb. The level of the p105Rb-regulated transcription factor, E2F1, is reduced, as is transcription of a variety of E2F1-regulated genes, including B-myb. Thus, the p53 growth inhibitory pathway has evidently not accumulated mutations in HeLa cells but rather appears intact. However, this pathway remains dormant, until it is mobilized by appropriate manipulations, such as the expression of the BPV E2 protein.
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PMID:Activation of the endogenous p53 growth inhibitory pathway in HeLa cervical carcinoma cells by expression of the bovine papillomavirus E2 gene. 863 1

While oncoproteins encoded by small DNA tumor viruses and Epstein-Barr virus (EBV) latent antigens facilitate G1/S progression, the EBV lytic switch transactivator Zta was found to inhibit growth by causing cell cycle arrest in G0/G1 in several epithelial tumor cell lines. Expression of Zta results in induction of the tumor suppressor protein, p53, and the cyclin-dependent kinase inhibitors, p21 and p27, as well as accumulation of hypophosphorylated pRb. Up-regulation of p53 and p27 occurs by post-transcriptional mechanisms while expression of p21 is induced at the RNA level in a p53-dependent manner. Inactivation of pRb by transient overexpression of the human papillomavirus E7 oncoprotein indicates that pRb or pRb-related proteins are key mediators of the growth-inhibitory function of Zta. These findings suggest that EBV plays an active role in redirecting epithelial cell physiology to facilitate the viral replicative program through a Zta-mediated growth arrest function.
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PMID:The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors. 865 72

We have recently reported that mutant but not wild-type (wt) p53 protein was ADP-ribosylated in primary rat cells overexpressing the temperature-sensitive murine p53val135 gene. To examine whether the lack of susceptibility to modification is a specific feature of p53val135 adopting wt conformation or rather a general property of this tumor suppressor protein, we have studied ADP-ribosylation of wt p53 of different origin in vitro using semi-purified poly(ADP-ribose) transferase (pADPRT). In vitro pADPRT modified human and mouse wt p53 and p53val135. Under limiting substrate concentration, the molar mass of ADP-ribosylated p53 was only slightly altered. Chase experiments with high NAD concentration resulted in the formation of poly(ADP-ribosyl)ated p53 protein shifted to 64 kD. However, preincubation of wt p53 proteins with a p53 consensus sequence resulting in complex formation abolished the modification of wt p53. This indicates that in the cellular environment the specific DNA binding of wt p53 prevents its covalent modification by poly(ADP-ribose).
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PMID:ADP-ribosylation of wild-type p53 in vitro: binding of p53 protein to specific p53 consensus sequence prevents its modification. 869 40


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