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

The overexpression of the oncogene product MDM2 is often observed in human breast cancer cells, especially in estrogen receptor (ER)-positive ones. To study the role of MDM2 protein in ER-positive breast cancer, we have established cell lines derived from MCF-7 which stably express increased and decreased levels of MDM2 by transfection of a mammalian expression vector containing human mdm2 cDNA in sense and antisense orientations, respectively. Interestingly, MDM2 overexpression in MCF-7 cells afforded a remarkable growth advantage under estradiol (E2)-supplemented condition. Then, we analyzed the expression of p53, which is an important regulator of growth and the cell cycle. Unexpectedly, the p53 accumulation induced by E2 was remarkably higher in MCF-7 cells stably overexpressing MDM2 than in the parent MCF-7 cells. On the other hand, reduction of MDM2 suppressed the E2-induced increase in p53 protein. Moreover, mdm2 antisense oligonucleotides prevented E2-induced accumulation of p53. In the steady state, the cellular levels of p53 were also correlated with those of MDM2. These interactions are not consistent with the well-known role of MDM2, which acts as a negative regulator for p53 by inhibiting its function and promoting its rapid degradation. These results suggest that MDM2 may regulate the expression of p53 in the steady state and in response to E2 in breast cancer cells, and imply a novel and important role of MDM2 during breast carcinogenesis.
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PMID:Overexpression of MDM2 in MCF-7 promotes both growth advantage and p53 accumulation in response to estradiol. 1018 92

The newly identified p53 homolog p73 can mimic the transcriptional activation function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo and in vitro. Wild-type but not mutant MDM2, expressed in human p53 null osteosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driven by the MDM2 promoter-derived p53RE motif as measured in transient-transfection and chloramphenicol acetyltransferase assays and also inhibited p73-induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73alpha and p73beta stimulated the expression of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activated by p73 and, in turn, negatively regulates the function of this activator through a mechanism distinct from that used for p53 inactivation.
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PMID:MDM2 suppresses p73 function without promoting p73 degradation. 1020 51

The MDM2 protein regulates the functional activity of the p53 tumor suppressor through direct physical association. Signals that control MDM2 expression are poorly understood but are likely to play an important role in the regulation of p53 activity. We show here that the half-life of MDM2 protein is shorter in proliferating than in quiescent peripheral blood mononuclear cells. We also demonstrate that MDM2 protein half-life is extended in some, but not all, p53 mutant human leukemic cell lines. In at least one of these p53 mutant lines, increased MDM2 protein stability is associated with higher amounts of MDM2 protein. Moreover, we demonstrate that MDM2 protein accumulates to a much greater extent in proteasome inhibitor-treated cells containing unstable MDM2 than in cells possessing stable MDM2. These results demonstrate that MDM2 expression is regulated by events that control the stability of the protein and suggest that the normal regulation of MDM2 turnover can be altered in tumor cell lines.
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PMID:The pathway regulating MDM2 protein degradation can be altered in human leukemic cells. 1023 88

Wild-type p53 is degraded in part through the ubiquitin proteolysis pathway. Recent studies indicate that MDM2 can bind p53 and promote its rapid degradation although the molecular basis for this degradation has not been clarified. This report demonstrates that MDM2 can promote the ubiquitination of wild-type p53 and cancer-derived p53 mutants in transiently transfected cells. Deletion mutants that disrupted the oligomerization domain of p53 displayed low binding affinity for MDM2 and were poor substrates for ubiquitination. However, efficient MDM2 binding and ubiquitination were restored when an oligomerization-deficient p53 mutant was fused to the dimerization domain from another protein. These results indicate that oligomerization is required for p53 to efficiently bind and be ubiquitinated by MDM2. p53 ubiquitination was inhibited in cells exposed to UV radiation, and this inhibition coincided with a decrease in MDM2 protein levels and p53.MDM2 complex formation. In contrast, p53 dimerization was unaffected following UV treatment. These results suggest that UV radiation may stabilize p53 by blocking the ubiquitination and degradation of p53 mediated by MDM2.
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PMID:Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2. 1034 17

The expression of MDM2 protein in betel and tobacco related oral malignancies in Indian population, its relationship to clinicopathological parameters and p53 protein expression was investigated. Sixty five oral squamous cell carcinomas (SCCs), 33 premalignant lesions (leukoplakia) and 30 normal oral tissues were assessed by immunohistochemical analysis. MDM2 protein was overexpressed in 51/65 (78%) oral SCCs and 17/33 (52%) premalignant lesions; 11/23 hyperplastic lesions and 6/10 dysplastic lesions. mdm2 gene amplification is an infrequent event in oral tumorigenesis. Elevation in the level of MDM2 protein not only in oral SCCs but also in premalignant lesions suggests that altered MDM2 expression is an early even in the pathogenesis of oral neoplasia. The hallmark of the study was the significant association of MDM2 expression with the p53 protein accumulation in 16/33 (49%) oral premalignant lesions (p = 0.001) and 39/65 (60%) malignant lesions (p = 0.021), suggesting an active role for MDM2 in binding and inactivating p53 in oral tumorigenesis. Further, significant association of MDM2/p53 co-expression was observed with advanced tumour stage (p = 0.0009), as well as lymph node metastasis (p = 0.0325) features associated with aggressive tumour behaviour and poor prognosis. Discordant MDM2+/p53-phenotype was observed in 12/65 (18%) oral SCCs suggesting a p53-independent role for MDM2 in the pathogenesis of a subset of oral carcinomas. In conclusion, alterations in MDM2 and p53 expression are early events likely to be involved in preinvasive stages in oral tumorigenesis and may be indicative of a 'gain of function' phenotype with more aggressive characteristics.
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PMID:MDM2/p53 co-expression in oral premalignant and malignant lesions: potential prognostic implications. 1043 58

High-risk human papillomaviruses are causally associated with cervical cancer. Two viral oncogenes, E6 and E7, are expressed in most cervical cancers, and these genes cause cancer when expressed in experimental animals. The E6 protein targets the p53 tumor suppressor for degradation, while the E7 protein inactivates the retinoblastoma susceptibility protein (pRb), in part by stimulating its degradation. In contrast, expression of E7 in the absence of E6 leads to stabilization of p53. Here we show that E7 stabilizes p53 in mouse embryo fibroblasts lacking p19(ARF). The stable p53 is active as a transcriptional activator, as evidenced by the increased expression of the p53-responsive mdm2 gene. Normally, MDM2 protein inhibits p53 function in an autoregulatory loop. Regulation of p53 by MDM2 is required for murine development as well as for proliferation of cultured human fibroblasts. However, E7-expressing human fibroblasts continue to divide even though E7 abrogates the ability of MDM2 and p53 to bind. Furthermore, E7-expressing cells are not more sensitive to UV light, an agent that has been reported to induce apoptosis mediated by p53. These results indicate that in addition to inhibiting the ability of MDM2 to regulate p53, E7 must block signaling steps downstream of p53 to allow cell division.
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PMID:The E7 oncoprotein of human papillomavirus type 16 stabilizes p53 through a mechanism independent of p19(ARF). 1043 49

Overexpressed MDM2 inactivates wild-type (wt) p53 in various human tumors. However, whether and how the wild-type p53 can be activated by anticancer drug treatment in the presence of excess MDM2 is still unclear. In the present study, we showed that the topoisomerase II inhibitor of widely used anticancer drugs etoposide and doxorubicin activated wt p53 in BL2, a Burkitt's lymphoma cell line which overexpressed MDM2. Activation of p53 was followed by apoptosis in BL2 cells, while the same drug treatment did not induce apoptosis in Raji cells, another Burkitt's lymphoma cell line which carried mutant p53. Activation of p53 was accompanied by phosphorylation of p53 at Ser-15 and elevated p21 and MDM2, both of which were at least partly blocked by wortmannin, a kinase inhibitor against proteins with a PI3 kinase domain. Although MDM2 protein was rapidly cleaved and degraded after anticancer drug treatment, cotreatment with caspase inhibitor Z-VAD blocked degradation, while wt p53 remained activated, suggesting MDM2 degradation not to be essential for the activation of p53. Treatment with proteasome inhibitor stabilized p53 without being further phosphorylated. This p53 was co-immunoprecipitated with MDM2, but p53 activated by etoposide or doxorubicin barely complexed with MDM2. These results suggest that the wild-type p53 in MDM2-overexpressing cells can be activated by anticancer drugs through phosphorylation of p53, alleviating inhibitory action by MDM2, and activating caspases which in turn downregulates MDM2. The activation of p53 in MDM2-overexpressing tumor cells, which does not require the downregulation of MDM2, may have important implications in cancer therapy.
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PMID:Activation of p53 in MDM2-overexpressing cells through phosphorylation. 1054 21

In order to understand better the possible role of cell-cycle regulating molecules in the pathogenesis of Hodgkin's disease (HD), the immunohistochemical distribution pattern of p16INK4A was investigated and compared with pRb, p53, and MDM2 protein status in 44 HD cases. Our findings were correlated to the presence of Epstein-Barr virus as detected by RNA in situ hybridization and clinicopathological parameters. p16INK4A protein immunoreactivity was found in all 44 cases with a proportion of Hodgkin-Reed-Sternberg (HRS) cells ranging from 30 to 90%. In 93% of the cases studied, pRb was detected in HRS, whereas all cases showed overexpression of p53. Almost all specimens (98%) were MDM2-positive as evaluated by 1B10 and/or IF2 monoclonal antibodies. EBER 1/2-transcripts were detected in 31.8% (14 of 44) of the examined samples. A significant correlation was observed between immunoreactivity of p16INK4A and MDM2 and the number of HRS cells (P = .0012 and P = .018, respectively). In a subgroup of cases, with p16INK4A expression in more than 50% of HRS cells, the percentage of pRb-positive neoplastic cells was inversely related to that of p16-positive ones (P = .007). No clinicopathological parameters or clinical prognostic indicators, including duration of response to therapy, were statistically related to the expression levels of any of the four proteins investigated or the presence of Epstein-Barr virus. Our findings suggest that p16 and pRb are regularly expressed and that their pathway in cell-cycle machinery seems to be intact in HD. However, further investigation is needed to shed light on the involvement of cell-cycle molecules in Hodgkin's lymphomagenesis and longer patient follow-up is required for conclusive prognostic correlation.
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PMID:p16INK4A is regularly expressed in Hodgkin's disease: comparison with retinoblastoma, p53 and MDM2 protein status, and the presence of Epstein-Barr virus. 1057 4

The MDM2 oncoprotein has been shown to inhibit p53-mediated growth arrest and apoptosis. It also confers growth advantage to different cell lines in the absence of p53. Recently, the ability of MDM2 to arrest the cell cycle of normal human fibroblasts has also been described. We report a novel function for this protein, showing that overexpression of MDM2 promotes apoptosis in p53-deficient, human medullary thyroid carcinoma cells. These cells, devoid of endogenous MDM2 protein, exhibited a significant growth retardation after stable transfection with mdm2. Cell cycle distribution of MDM2 transfectants [medullary thyroid tumor (MTT)-mdm2] revealed a fraction of the cell population in a hypodiploid status, suggesting that MDM2 is sufficient to promote apoptosis. This circumstance is further demonstrated by annexin V labeling. MDM2-induced apoptosis is partially reverted by transient transfection with p53 and p19ARF. Both MTT and MTT-mdm2 cells were tumorigenic when injected into nude mice. However, the percentage ofapoptotic nuclei in tumor sections derived from MDM2-expressing cells was significantly higher relative to that in the parental cell line. MDM2-mediated programmed cell death is at least mediated by a down-regulation of the antiapoptotic protein Bcl-2. Protein levels of caspase-2, which are undetectable in the parental cell line, appear clearly elevated in MTT-mdm2 cells. Caspase-3 activation does not participate in MDM2-induced apoptosis, as determined by protein levels or poly(ADP-ribose) polymerase fragmentation. The results observed in this medullary carcinoma cell line show for the first time that the product of the mdm2 oncogene mediates cell death by apoptosis in p53-deficient tumor cells.
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PMID:The MDM2 oncoprotein promotes apoptosis in p53-deficient human medullary thyroid carcinoma cells. 1061 65

Hypoxia, a result of DNA-damaging agents such as ionizing radiation, induces the nuclear accumulation of the p53 tumor suppressor protein. However, unlike the effect in ionizing radiation, hypoxia readily induces the nuclear accumulation of p53 in HPV E6-infected cells. In HPV-infected cells, a key regulator of p53 protein levels is the E6 oncoprotein. In association with the endogenous cellular protein E6-associated protein (E6AP), E6 can accelerate the degradation of p53 under aerobic conditions. To better define the mechanism of p53 induction in E6-infected cells by hypoxia, we studied the expression and association of E6 and E6AP with p53 in vivo. We found that hypoxia did not alter the protein levels of E6 or E6AP as compared with those found under aerobic growth conditions, indicating that protein inhibition of E6 or E6AP alone is not sufficient to explain the increased accumulation of p53 under hypoxic conditions. However, p53 did fail to coprecipitate with E6AP under hypoxia, indicating that hypoxia uncouples the interaction of p53 with E6 and E6AP. We also present evidence to indicate that hypoxia decreases the expression of the endogenous cellular regulator of p53 protein, the human MDM2 protein, resulting in an inhibition of p53 export from the nucleus to the cytoplasm for degradation. Taken together, these results suggest that the hypoxic induction of p53 is attributable to the down-regulation of MDM2 protein levels and uncoupling of p53 from its interaction with the E6/E6AP complex.
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PMID:Hypoxia induces p53 accumulation through MDM2 down-regulation and inhibition of E6-mediated degradation. 1062 88


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