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)

To explore the biochemical functions of p53, we have initiated a search for cellular p53-binding proteins. Coprecipitation of three polypeptides was observed when cell lines overexpressing a temperature-sensitive (ts) p53 mutant were maintained at 32.5 degrees C (wild-type p53 activity, leading to growth arrest) but not at 37.5 degrees C (mutant p53 activity). One of these three proteins, designated p95 on the basis of its apparent molecular mass, was highly abundant in p53 immune complexes. We demonstrate herein that p95 is a p53-binding protein, which exhibits poor p53-binding in cells overproducing several distinct mutant p53 proteins. Yet, p95 associates equally well with both the wild-type (wt) and the mutant conformations of the ts p53 in transformed cells growth-arrested at 32.5 degrees C. On the basis of our findings we suggest that wt p53 activity increases p53-p95 complex formation and that such interaction may play a central role in p53 mediated tumour suppression.
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PMID:Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest. 160 Sep 43

Amplification of the MDM2 gene, which maps to chromosome band 12q13 and encodes a p53-binding protein, may result in functional inactivation of p53 and has been observed in various bone and soft tissue sarcomas. Published studies have included few cases of Ewing's sarcoma (ES) or peripheral neuroectodermal tumour (PNET), a tumour group in which alterations of the p53 pathway have so far not been extensively studied. We examined two ES cell lines, RD-ES and SK-ES-1, and 30 specimens from 27 patients (24 ES, 6 PNET; 19 primary, 4 local recurrence, 7 metastasis) for MDM2 gene amplification by Southern blot analysis. All 30 clinical specimens had been confirmed to contain sufficient ES/PNET DNA by the demonstration of a rearrangement of the t(11;22)-associated EWS gene using an EWS cDNA probe on the same blots. MDM2 gene amplification was detected in 3 of 30 specimens (10 per cent), including two ES and one PNET, but in neither of the cell lines. The three cases with amplification were morphologically typical primary tumours. Two of the three cases also showed co-amplification of the CDK4 gene, which encodes a cyclin-dependent kinase and also maps to band 12q13. Clinically, all three cases had metastatic disease at diagnosis, compared with only 1 of 15 MDM2-negative cases where the primary tumour was studied. The difference was statistically significant (P = 0.005), suggesting an association of MDM2 amplification with advanced stage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:MDM2 and CDK4 gene amplification in Ewing's sarcoma. 773 17

The human p53-binding protein murine double minute 2 (MDM2) is believed to function as a negative regulator of p53. The MDM2 gene was cloned and sequenced only recently and was found to be amplified in a variety of sarcomas. Although mutations in the p53 gene have been shown to occur in human breast carcinoma (HBC), no information is available on MDM2 gene expression in HBC. In this study we report for the first time that the MDM2 gene is differentially expressed in HBC. Our results demonstrate a correlation between the estrogen receptor (ER) status and the MDM2 mRNA levels. In contrast to the ER-negative cell lines, all the ER-positive cell lines were found to express higher levels of MDM2 mRNA. ER-positive ZR-75 cells express 30-fold higher levels of MDM2 mRNA than does the ER-negative cell line Hs578T. Estrogen enhanced albeit modestly the MDM2 mRNA levels in ER-positive MCF-7 cells. Estrogen enhancement of MDM2 mRNA levels was also observed in ER-negative MDA-MB-231 cells transfected with functional ERs. Our data thus suggest that estrogen may play an important role in HBC growth stimulation by modulating the expression of MDM2, which in turn may inactivate the p53 function.
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PMID:The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma. 832 31

The human homologue of the murine double minute 2 gene (MDM2), a p53-binding protein which may act as a regulator of p53 protein function, has recently been cloned. Initial studies of this gene in a variety of human tumors have shown frequent gene amplification in most types of sarcomas, including osteosarcomas. Amplification of the MDM2 gene may produce a functional inactivation of the p53 protein. To examine possible clinical or pathological correlates of MDM2 gene amplification in osteosarcoma, we studied 28 specimens on 26 patients with high grade osteosarcoma (16 primary, 11 metastatic, and 1 local recurrence) for MDM2 gene amplification by Southern blot analysis, using two MDM2 complementary DNA probes isolated by polymerase chain reaction. Four specimens (14%) showed amplification, including 3 metastases and 1 local recurrence. None of the primary osteosarcoma specimens had detectable MDM2 gene amplification. None of the specimens tested showed MDM2 gene rearrangement. In the present series, MDM2 gene amplification was detected significantly more frequently in metastatic or recurrent osteosarcomas than it was in primary osteosarcomas (P = 0.02). Our data suggest that MDM2 gene amplification may be associated with tumor progression and metastasis in osteosarcoma. Further investigation is warranted on the potential clinicopathological correlates of MDM2 gene amplification in osteosarcoma.
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PMID:MDM2 gene amplification in metastatic osteosarcoma. 841 41

We recently reported the identification of a mouse cDNA encoding a new p53-associating protein that we called Mdmx because of its structural similarity to Mdm2, a well-known p53-binding protein. Here we report the isolation of a cDNA encoding the human homolog of Mdmx. The ORF of the cDNA encodes a protein of 490 amino acids, 90% similar to mouse Mdmx. The homology between Mdmx and Mdm2 is most prominent in the p53-binding domain and the putative metal-binding domains. The Mdmx protein, which, based on SDS-PAGE, has a MW of 80 kDa, can bind p53 in vitro. The human MDMX gene is transcribed in all tissues tested, with high levels in thymus. By fluorescence in situ hybridization analysis we mapped the mouse mdmx gene to chromosome 1 (region F-G) and the human MDMX gene to chromosome 1q32.
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PMID:Isolation and identification of the human homolog of a new p53-binding protein, Mdmx. 922 70

Alteration of the p53 gene is the most frequent event reported in human cancer, and p53 mutations have been observed in various neoplasms, including certain forms of skin cancer. Therefore, we postulated that p53 may also be involved in Kaposi's sarcoma associated with AIDS (AIDS-KS). Expression of the p53 gene was examined in freshly isolated tumor biopsy specimens from 15 patients with AIDS-KS. p53 mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in both the AIDS-KS tumors and in normal skin control samples. p53 protein was detected in 4 of the 15 AIDS-KS specimens by immunohistochemical staining. Single-strand conformation polymorphism analysis PCR-products (PCR-SSCP) was used for detection of mutations of the p53 gene. One of the p53 positive AIDS-KS samples showed mobilized shifts in exon 6 suggestive of a mutation. Sequencing data showed the mutation to be located in codon 210. We examined other mechanisms that could stabilize p53 protein. SV40 large T antigen and adenovirus E1B protein were not found in the AIDS-KS specimens. MDM2, a p53-binding protein, was also detected in five of the AIDS-KS specimens, two of which also contained p53-positive cells. These observations suggest that the tumor suppressor gene p53 may be involved in the pathogenesis of AIDS-KS.
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PMID:Expression and mutation of the tumor suppressor gene p53 in AIDS-associated Kaposi's sarcoma. 965 Jul 11

p53 exerts important physiological functions in cell-cycle control, gene regulation, cell differentiation, apoptosis and tumor suppression by interacting with many cellular proteins. Using the yeast two-hybrid system, we screened a HeLa cDNA library and identified a novel gene encoding a p53-binding protein (p53BP3). The full-length cDNA of p53BP3 was isolated from a HeLalambdagt10 cDNA library. This predicted protein was composed of 815 amino acids. Sequence analysis indicated that p53BP3 contained two bipartite nuclear localization signals and was confirmed to be a nuclear protein. FISH mapping results showed that this novel gene was located at human chromosome 12, region p11.2-p12.1. Northern blot analysis suggested that p53BP3 was broadly expressed in human tissues. A further study showed that p53BP3 had a homologue in mouse.
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PMID:Identification of a novel gene encoding a p53-associated protein. 1041 37

The p53 tumor suppressor protein is stabilized in response to cellular stress, resulting in activation of genes responsible for either cell cycle arrest or apoptosis. The cellular pathway for releasing normal cells from p53-dependent cell cycle arrest involves the Mdm2 protein. Recently, a p53-binding protein with homology to Mdm2 was identified and called MdmX. Like Mdm2, MdmX is able to bind p53 and inhibit p53 transactivation; however, the ability of MdmX to degrade p53 has yet to be examined. We report here that MdmX is capable of associating with p53 yet is unable to facilitate nuclear export or induce p53 degradation. In addition, expression of MdmX can reverse Mdm2-targeted degradation of p53 while maintaining suppression of p53 transactivation. Using a series of MdmX deletions, we have determined that there are two distinct domains of the MdmX protein that can stabilize p53 in the presence of Mdm2. One domain requires MdmX interaction with p53 and results in the retention of both proteins within the nucleus and repression of p53 transactivation. The second domain involves the MdmX ring finger and results in stabilization of p53 and an increase in p53 transactivation. The potential basis for stabilization and increased p53 transactivation by the MdmX ring finger domain is discussed. Based on these observations, we propose that the MdmX protein may function to maintain a nuclear pool of p53 protein in undamaged cells.
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PMID:MdmX protects p53 from Mdm2-mediated degradation. 1062 57

Regulation of p53 protein activity is required for normal embryogenesis, tumor suppression, and cellular response to DNA damage. Here we report that loss of mdmx, a p53-binding protein, results in midgestational embryo lethality, a phenotype that is completely rescued by the absence of p53. Mice homozygous for both mdmx and p53 null mutations are viable and appear developmentally normal. Fibroblasts derived from embryos with reduced mdmx expression demonstrate a decreased growth rate and increased UV-induced apoptosis compared with wild-type cells and contain elevated levels of p53 and several p53 target proteins including the proapoptotic bax protein. These observations demonstrate that mdmx functions as a critical negative regulator of p53 in vivo.
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PMID:mdmx is a negative regulator of p53 activity in vivo. 1203 37

A complex of the DNA-binding domain of the tumour suppressor p53 bound to the BRCT domains of the p53-binding protein (53BP1) has been prepared and purified. Single crystals have been obtained using the microbatch technique with polyethylene glycol 4 kDa and ammonium sulfate. Crystals diffract X-rays to beyond 2.3 A and belong to the space group P2(1)2(1)2(1). Several complete data sets have been collected from a number of crystals, each with different unit-cell parameters. Partial structures have been produced by successful placement of two copies of the p53 core region into the asymmetric unit. There is clear evidence for the binding protein and a complete structure determination is under way.
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PMID:Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor. 1235 27


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