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)

MDM-2 is one of the target genes of the p53 tumor suppressor protein. Its best characterized function is found in the inhibition of p53's ability to modulate transcription. Deregulated expression of MDM-2 could thus at least partially substitute for p53 mutation in the process of tumorigenesis. We show here that MDM-2 is highly expressed in biopsies of normal human skin or in vitro reconstituted human skin. The protein is detected in the nucleus of keratinocytes throughout the different layers of the epidermis and in reconstituted skin as early as the two to three cell layer stage. The 90 kiloDalton (kD) protein is one of the major forms detected in Western blot experiments. MDM-2 is detected in skin reconstituted from keratinocytes in which p53 is inactivated by mutation or degradation by E6 protein, providing evidence that MDM-2 expression in the skin can occur in the absence of wild type p53. Moreover, we found no correlation between the p53 status and MDM-2 expression levels in a series of basal and squamous cell carcinomas or Bowen diseases. Our data provide first evidence for the expression of MDM-2 in a differentiated adult tissue.
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PMID:MDM-2 protein is expressed in different layers of normal human skin. 907 Jun 62

Each human papillomavirus (HPV) type is genotypically distinct and infects epithelial cells at unique anatomic sites. Among the HPV types described, a subgroup is associated with genital disease and a subset of these is found in 90% of genital cancers. Although in benign infections the viral genome is present as an episome, in cancers it is integrated. The integration event invariably results in the expression of two viral proteins, E6 and E7. These two proteins are capable of transforming cells individually and cooperate to immortalize primary human epithelial cells. Molecular analysis has revealed that the E6 protein encoded by the HPV "high risk" types prevalent in cancers forms a tripartite complex with the p53 tumor suppressor protein and a cellular protein termed E6-AP, resulting in the degradation of p53. The E7 protein encoded by "high-risk" HPV types shows high-affinity association with the retinoblastoma tumor suppressor, pRb. The E7 protein associates also with other cellular factors known to play a role in cell cycle regulation. This review discusses the evidence, molecular and biological, in vitro and in vivo, supporting a direct role for the "high-risk" HPV type encoded E6 and E7 proteins in cervical carcinogenesis.
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PMID:The oncogenic role of human papillomavirus proteins. 910 94

The ability of the E6 protein from high risk human papillomaviruses (HPVs) to degrade p53 via the ubiquitin pathway plays a major role in the development of cervical carcinomas. We have previously generated cell hybrids between a p53 null peripheral neuroepithelioma (PNET) cell line and a cervical carcinoma HeLa cell line which exhibits efficient E6-mediated degradation of p53. All of the resulting hybrids expressed HPV 18 E6 from the HeLa parent and some of the hybrids additionally expressed HPV 16 E6. Surprisingly, in spite of abundant E6 expression, the hybrids expressed relatively high steady-state levels of the wild-type p53 protein. We then examined the hybrids to determine whether other components of the E6-mediated degradation pathway were missing or nonfunctional. Specifically, we determined that the E6-associated protein (E6-AP), essential for E6-mediated degradation, was expressed. We further verified that these hybrids had a functional ubiquitination pathway, which suggests that this phenomenon is not due to a general defect in this pathway. We therefore conclude that other unidentified, possibly cell-specific factors can play a role in the E6-mediated degradative process and may act to inhibit this process.
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PMID:Failure of HPV E6 to rapidly degrade p53 in human HeLa x PNET cell hybrids. 913 68

Human papillomaviruses (HPVs) express various gene products, such as E6 protein which complexes with the p53 tumor suppressor protein and therefore diminishes p53-related regulatory mechanisms. This interaction is assumed to be HPV type-specific as "high risk" or oncogenic HPV types have more affinity for p53 binding than their "low risk" or non-oncogenic counterparts. Furthermore, HIV infection is believed to activate latent HPV infection and transcription via direct and indirect interaction with HPVs as well as cellular genes and functions. Accordingly, we carried out experiments on biopsies which originated from condylomas ("low risk" HPVs), HIV-positive condylomas (infection with multiple "low risk" and "high risk" HPVs) and anogenital squamous cell carcinomas (SCCs, "high risk" HPV infection). Using reverse transcription PCR (RT-PCR) and western immunoblotting, mRNA and protein levels of p53 and genes regulated by p53, such as mdm2 and WAF1/CIP1 were determined. We found that the presence of HPV can diminish p53 and increase WAF1/CIP1 and mdm2 protein levels. There were no significant differences in this regulation between "low risk" and "high risk" lesions. Our data suggest that these HPV-mediated cellular effects are not type-specific, and they might be part of a viral-cell interaction or represent a cellular defense mechanism against the virus. However, HIV-seropositivity renders HPV lesions containing both "low risk" and "high risk" significantly different. This may be due to the alteration of HPV-controlling cellular pathways by HIV tat and/or activation of cellular pathways different from HIV-negative counterparts. Either possibility is of great interest and needs further verification.
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PMID:p53, WAF1/CIP1 and mdm2 expression in skin lesions associated with human papillomavirus and human immunodeficiency virus. 913 86

Using a plasmid substrate which integrates into the genome, we determined that the rate of homologous recombination was suppressed by p53. Human tumor cell lines, mutant or null for p53 had recombination rates 10000-times greater than primary fibroblasts. When isogenic cell pairs from tumor cells or primary fibroblasts were compared, differing only in one genetic change which inactivated p53, the recombination rate increased > 100-fold. Functional inactivation of p53 by dominant mutant p53, by large T antigen of SV40 virus, by E6 protein of human papilloma virus, or by genetic deletion led to the same result. Our results suggest that p53 suppresses spontaneous homologous recombination, and that p53 is not required for recombination to proceed. The mechanism of recombination suppression may be related to the reported association of p53 with Rad 51, but the functional consequences of this association are not yet established. It is suggested that suppression of homologous recombination is the means by which p53 maintains genetic stability.
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PMID:Inactivation of p53 results in high rates of homologous recombination. 915 Mar 91

Although human papillomavirus type 16 (HPV16) E6 protein has a transcription-modulatory activity for a wide variety of viral promoters, a cellular target for this activity of E6 has not yet been identified. In this study, using differential hybridization, we identified a mouse fibronectin (FN) gene as a putative cellular target whose expression is up-regulated by E6. Chloramphenicol acetyltransferase (CAT) assays with mouse and rat FN promoter-CAT fusion constructs indicated that HPV16 E6 transactivates the FN promoters in a p53-independent manner. Deletion and site-specific mutation analyses revealed that transactivation by HPV16 E6 depends upon a cyclic AMP response element (CRE) located at -160 relative to the start site of transcription. Gel retardation assays demonstrated that nuclear extracts from the HPV16 E6-expressing cells, compared to those from parental 10T1/2 cells, have increased binding activity to the CRE. Antibodies against c-Jun and ATF-2 disrupted this binding activity. These data indicate that HPV16 E6 transcriptionally modulates FN gene expression via the CRE by inducing the binding of the protein complexes, probably including c-Jun and ATF-2, to the CRE.
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PMID:Human papillomavirus type 16 E6 protein transcriptionally modulates fibronectin gene expression by induction of protein complexes binding to the cyclic AMP response element. 915 19

Cervical cancer is the second leading cause of death from cancer in women worldwide, and recent epidemiological studies have strongly implicated the sexually transmitted human papillomavirus (HPV) as a causative agent. The ability of high-risk HPVs to contribute to malignant progression seems to depend on expression of the viral E6 and E7 oncogenes. The E6 oncoprotein forms a complex with the cellular tumor suppressor protein p53, leading to degradation of p53 via ubiquitin-dependent proteolysis. Thus, E6 expression results in the loss of p53 function in cells, including stimulation of apoptosis and inhibition of the expression of the antiapoptotic protein bcl-2. Recently, we found increased bcl-2 expression in cervical carcinoma cell lines containing mutated or E6-inactivated p53 (X. L. Liang, S. Mungal, A. Ayscue, J. D. Meissner, P. Wodnicki, G. Gordon, S. Lockett, and B. Herman. J. Cell. Biochem., 57: 509-520, 1995). Based on these findings, we examined Papanicolaou smears from 94 women with varying degrees of cervical disease for the presence or absence of p53, HPV-16/18 E6, and bcl-2 proteins using immunofluorescence microscopy. Our findings indicate that there is a statistically significant, inverse association between the presence of p53 and invasive cervical disease [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7]. Moreover, the odds of being diagnosed with an invasive stage of cervical cancer were 3.7 times higher (95% CI, 1.6-8.8) for women positive for the E6 protein and 17 times higher (95% CI, 5.5-58.3) for women positive for the bcl-2 protein compared with women negative for E6 and bcl-2. Women with invasive cervical cancer were also 4.59 times more likely to test positive for the presence of more than one marker (95% CI, 1.8-11.8). Chi(2) analysis demonstrated a strong association between the presence of E6 and bcl-2 (P < 0.001) as well as between the presence of E6 of bcl-2 and diagnosis (P = 0.015 and < 0.001, respectively). In the multivariate analysis, the presence of bcl-2 (OR, 18.8; 95% CI, 5.5-67.8) and age at diagnosis (> or = 50 years; OR, 7.8; 95% CI, 2.5-24.5) showed significant association with Invasive cervical disease. These findings indicate that: (a) the presence of the bcl-2 protein is strongly associated with the development of invasive cervical disease: (b) the pattern of the presence of high-risk HPV-E6, p53, and bcl-2 proteins may be useful for identifying women at increased risk for the development of invasive cervical cancer; and (c) a defect in apoptosis may partially underlie the development of cervical cancer.
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PMID:The presence of human papillomavirus-16/-18 E6, p53, and Bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer. 916 97

In most instances, the transfer of ubiquitin to target proteins is catalyzed by the action of ubiquitin protein ligases (E3s). Full-length cDNAs encoding murine E6-associated protein (mE6-AP) as well as Nedd-4, a protein that is homologous to E6-AP in its C terminus, were cloned. Nedd-4 and mouse E6-AP are both enzymatically active E3s and function with members of the UbcH5 family of E2s. Mouse E6-AP, like its human counterpart, ubiquitinates p53 in the presence of human papilloma virus E6 protein, while Nedd-4 does not. Consistent with its role in p53 ubiquitination, mE6-AP was found both in the nucleus and cytosol, while Nedd-4 was found only in the cytosol. Binding studies implicate a 150-amino acid region that is 40% identical between mE6-AP and Nedd-4 as a binding site for the C-terminal portion of an E2 enzyme (UbcH5B). Nedd-4 was determined to have a second nonoverlapping E2 binding site that recognizes the first 67 amino acids of UbcH5B but not the more C-terminal portion of this E2. These findings provide the first demonstration of physical interactions between mammalian E2s and E3s and establish that these interactions occur independently of ubiquitin and an intact E3 catalytic domain. Furthermore, the presence of two E2 binding sites within Nedd-4 suggests models for ubiquitination involving multiple E2 enzymes associated with E3s.
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PMID:Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases. 918 27

The human papillomavirus type 16 E6 protein exerts a transforming activity through inactivation of tumor suppressor p53. Recently E6 has been shown to have additional transforming activities independent of p53. E6 is able to transactivate or repress several specific viral promoters. However, underlying molecular mechanisms and cellular target genes for the activity are not well understood. Using a differential hybridization technique, we identified the prothymosin alpha gene as a cellular target of E6 transactivation. E6 was able to transactivate the prothymosin alpha promoter in H358 cells lacking p53 and in C33A cells harboring a mutant p53 allele. Disruption of the E-box in intron 1 of the prothymosin alpha promoter abolished the responsiveness to E6. Then we determined if E6 up-regulates the expression of Myc, by which the prothymosin alpha promoter is transactivated through the E-box. We found that E6 is also able to transactivate the c-myc promoter in H358 cells and in C33A cells. These results suggest that E6 is able to transactivate the c-myc promoter independently of p53, and that the prothymosin alpha promoter is subsequently transactivated by Myc.
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PMID:Transactivation of prothymosin alpha and c-myc promoters by human papillomavirus type 16 E6 protein. 918 88

Burkitt's lymphoma (BL) cell lines carry a translocated c-myc gene and, in 60-80% of cases, exhibit mutations in the p53 tumor suppressor gene. We examined the potential role of the p53 gene in BL tumorigenicity using an in vitro assay that measures p53-dependent cell cycle arrest in the G1 phase of the cell cycle and an in vivo athymic murine model that detects differences in the tumorigenicity of BL cell lines. A highly significant inverse correlation was found between the ability of BL cells to arrest in G1 after irradiation and their tumorigenicity in athymic mice, consistent with the notion that loss of p53 function is associated with increased tumorigenicity. Inactivation of wild-type (wt) p53 function by expression of the human papillomavirus E6 protein in the AG876V BL cell line, which carries both wt and mutant p53 proteins, rendered the cell line significantly more tumorigenic in athymic mice. Transfection of the wt p53 gene into the p53 mutant and highly tumorigenic BL-41 cell line caused it to acquire wt p53 function and rendered it less tumorigenic in mice. In addition to confirming a role for the loss of p53 function in tumor progression, the data demonstrate that wt p53 protein can reduce BL tumorigenicity in vivo.
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PMID:Role of the p53 tumor suppressor gene in the tumorigenicity of Burkitt's lymphoma cells. 919 33


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