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)

Although mutations of the p53 gene are the most common genetic alteration in human tumors, they are relatively rare in cervical carcinomas, possibly because human papillomaviruses of the oncogenic type encode for an oncoprotein that leads to the ubiquitin-mediated destruction of p53. An important mediator of p53-induced cell-cycle arrest is p21waf1/cip1, and although several studies evaluated invasive and preinvasive cervical lesions for p53 expression, none has studied expression of this important downstream effector. We examined normal cervical squamous epithelium, squamous cell carcinomas, and a range of preinvasive cervical lesions for expression of p53, p21waf1/cip1, and the proliferation-associated antigen, Ki-67, by immunohistochemical analysis. p53 expression was absent in normal squamous epithelium and all dysplasias regardless of severity, consistent with the presence of predominantly wild-type p53. Invasive carcinomas were mostly negative but contained occasional small nests of cells immunoreactive for p53. p21waf1/cip1, on the other hand, was expressed in all normal squamous epithelium and all preinvasive and invasive lesions. In normal squamous epithelium, the basal and immediate parabasal layers were negative, with the early differentiating layers positive. Expression was increased in dysplasias compared with normal squamous epithelium, both in number of immunoreactive nuclei and intensity of staining. The highest expression was seen in high-grade dysplasias and invasive carcinomas. Ki-67 expression also increased with increasing severity of the lesion, but p21waf1/cip1 and Ki-67 seemed to be expressed in different cells, a fact that was confirmed by double immunohistochemical staining for these two proteins on the same sections. This paradoxical increase in p21waf1/cip1 expression and mutually exclusive expression might be related to the role of p21waf1/cip1 in differentiation.
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PMID:p53-independent expression of p21waf1/cip1 in preinvasive and invasive squamous neoplasms of the uterine cervix. 919 75

The E6 proteins originating from the tumour-associated Human Papillomavirus (HPV) types 16 and 18 have been shown to bind to and target the tumour suppressor protein, p53, for ubiquitin-mediated degradation. However, in cell lines derived from cervical neoplasias, the predominant early region transcripts are spliced and encode truncated forms of E6, termed E6*. We report here that HPV-18 E6* protein will interact both with the full-length E6 proteins from HPV-16 and HPV-18 and also with E6-AP, and subsequently blocks the association of full length E6 protein with p53. We also show that, as a result of this block, E6* can inhibit E6-mediated degradation of p53 both in vitro and in vivo. The biological consequences of this are increased transcriptional activity on p53-responsive promoters and an inhibition of cell growth in cells transfected with E6*. This is the first report of a potential biological function for this polypeptide and may represent a means by which HPV is able to modulate the activity of the full-length E6 protein with respect to p53 during viral infection.
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PMID:Alternatively spliced HPV-18 E6* protein inhibits E6 mediated degradation of p53 and suppresses transformed cell growth. 923 60

The E6 protein is a major transforming protein of many types of papillomaviruses. Mechanistically, the best characterized E6 proteins are those of the high-risk genital HPVs (e.g. HPV-16 and 18 E6), which function, at least in part, by inactivating the p53 tumor suppressor protein. Biochemical studies have shown that this occurs by targeted degradation of p53, dependent on the E6-AP ubiquitin-protein ligase. The model that has emerged from E6/E6-AP-dependent p53 degradation has provided insight into both HPV-associated carcinogenesis and the problem of substrate specificity of the ubiquitin system. Several observations suggest that the high-risk HPV E6 proteins may also have activities in addition to inactivation of p53.
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PMID:Mechanism of HPV E6 proteins in cellular transformation. 928 24

Mutations in p53 were detected in 11/23 (48%) of non melanoma skin cancers in renal allograft recipients and in 5/8 (63%) of sporadic tumours from immune competent patients. 9/12 (75%) of mutations in transplant patients and all 5 mutations in non transplant tumours were consistent with damage caused by ultraviolet (u.v.) irradiation. DNA sequences, predominantly of the epidermodysplasia verruciformis (EV) subgroup, were detected in 9/23 (39%) of transplant tumours and in 2/8 (25%) of eight non-transplant tumours. There was no relationship between HPV status and p53 mutation, HPV DNA being present in 5/16 (31%) of tumours with p53 mutation and 6/15 (40%) of tumours lacking p53 mutation. These data are consistent with an important role for sunlight in the development of post-transplant skin cancer, and with limited functional data suggesting that E6 proteins of the cutaneous and EV-related papillomaviruses do not target p53 for ubiquitin-mediated degradation.
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PMID:p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. 934 8

Common necessity for all papillomaviruses is to induce DNA synthesis in quiescent cells. This is commonly achieved by the E7 gene product, which interferes with the function of members of the retinoblastoma family controlling transition from the G1-phase to the S-phase of the cell cycle. Uncontrolled entry into S-phase activates, however, negative growth control signals which have to be bypassed to achieve production of progeny viruses. In addition to inherent activities of the E7 protein, high risk genital types encode an E6 protein that overcomes p53-mediated G1-arrest and apoptosis in concert with the cellular factor E6AP by targeting p53 for the enhanced ubiquitin-dependent degradation. The key question, which of these functions of genital E6 and E7 proteins is responsible for the carcinogenic phenotype, is still not completely answered. In contrast to high risk genital types no immortalizing or transforming activities have been found for the E7 proteins of the high risk cutaneous HPV8 and 47. On the other hand the ability of the E6 protein to transform established rodent fibroblasts seems to be a property shared by high risk genital and cutaneous types. To examine the existence of a common E6-mediated transforming pathway for both virus groups we compared the properties of the cutaneous E6 proteins with already known functions of E6 proteins of genital viruses. For this we analyzed the E6 proteins of low nak and high risk cutaneous and genital papillomaviruses with respect to cell transformation, to their abilities to bind, degradate, and influence the activity of human p53, and to bind E6AP. The results of our study demonstrate a clear lack of interaction between the transforming E6 proteins of HPV1 and HPV8 and both cellular proteins p53 and E6AP. In contrast, we found E6AP-independent binding of HPV16 E6 and HPV6 E6 to p53, although both proteins were different in their transforming potential. Of all four proteins investigated, only HPV16 E6 was able to bind to p53 and E6AP and to induce degradation of the p53 protein in the reticulocyte system. When we investigated in frame deletion mutants of the E6 protein of HPV16 for their abilities to bind to p53 or E6AP, degradate, and inhibit the transactivation function of p53 and to transform rodent fibroblasts, no correlation between the different activities could be found. Mutants still able to bind p53 and E6AP lacked transforming ability and other mutants that were transformation-competent were deficient in p53 and E6AP bindings.
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PMID:A comparative analysis of the interactions of the E6 proteins from cutaneous and genital papillomaviruses with p53 and E6AP in correlation to their transforming potential. 942 53

Upon activation in response to cellular stress or DNA damage, the p53 tumor suppressor induces the expression of gene products involved in cell cycle arrest and apoptosis. Using the proteasome-specific inhibitors, MG132 (N-acetyl-L-leucinyl-L-leucinal-L-leucinal) and lactacystin, here we show that the p53-response proteins, bax and mdm2 as well as p21, are degraded by the ubiquitin-proteasome pathway in HeLa cells. MG132 also increased expression of the three proteins in cells that lack p53, showing that stabilization of the p53 response proteins is not due to increased levels of p53 itself. Increases in mdm2 protein levels by MG132 was accompanied by increases in polyubiquitinated forms of the proteins. Our results indicate that ubiquitin-dependent protein degradation influences the turnover of downstream targets of p53, therefore suggesting that the proteasome plays a role in regulating apoptosis and cell cycle arrest in response to p53.
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PMID:mdm2 and bax, downstream mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. 943 91

The human lymphoblastoid leukemic cell line (CCRF-CEM) was induced to differentiate with phorbol 12-myristate 13-acetate (PMA). During differentiation, assessed by monitoring the cluster of differentiation (CD) profile, the prosome (proteasomes, multi-catalytic proteinase) distribution and composition were studied by microscopy, flow cytometry and Western blot analysis. Changes in prosome subunits were monitored using 3 monoclonal antibodies anti-p23K, p29K and p31K. There were changes in the subcellular distribution of prosome antigens in PMA treated cells compared to untreated cells. The amount of cytoplasmic prosomal antigens decreased during the first three days of differentiation and the membrane antigens increased; meanwhile there was an increase of p53 and no change in actin protein levels. As mitotic cyclins are degraded by the ubiquitin pathway and therefore via the prosome, the decrease observed in differentiated cells suggests that prosomes are involved in the cell cycle and thus in cell proliferation.
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PMID:Subcellular distribution and profiles of prosomes (proteasomes-MCP) during differentiation of human lymphoblastic cell line. 944 40

The tumor suppressor p53 is degraded by the ubiquitin-proteasome system. p53 was polyubiquitinated in the presence of E1, UbcH5 as E2 and MDM2 oncoprotein. A ubiquitin molecule bound MDM2 through sulfhydroxy bond which is characteristic of ubiquitin ligase (E3)-ubiquitin binding. The cysteine residue in the carboxyl terminus of MDM2 was essential for the activity. These data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus-uninfected cells which do not have E6 protein.
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PMID:Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. 945 May 43

Wild-type p53 is a short-lived protein which turns over very rapidly via selective proteolysis in the ubiquitin-proteasome pathway. Most p53 mutations, however, encode for protein products which display markedly increased intracellular levels and are associated with positive tumor-promoting activity. The mechanism by which mutation leads to impairment of ubiquitination and proteasome-mediated degradation is unknown, but it has been noted that many transforming p53 mutants are found in stable physical association with molecular chaperones of the hsp70 class. To explore a possible role for aberrant chaperone interactions in mediating the altered function of mutant p53 and its intracellular accumulation, we examined the chaperone proteins which physically associate with a temperature-sensitive murine p53 mutant. In lysate prepared from A1-5 cells grown under mutant temperature conditions, hsp70 coprecipitated with p53Val135 as previously reported by others, but in addition, other well-recognized elements of the cellular chaperone machinery, including hsp90, cyclophilin 40, and p23, were detected. Under temperature conditions favoring wild-type p53 conformation, the coprecipitation of chaperone proteins with p53 was lost in conjunction with the restoration of its transcriptional activating activity. Chaperone interactions similar to those demonstrated in A1-5 cells under mutant conditions were also detected in human breast cancer cells expressing two different hot-spot mutations. To examine the effect of directly disrupting chaperone interactions with mutant p53, we made use of geldanamycin (GA), a selective hsp90-binding agent which has been shown to alter the chaperone associations regulating the function of unliganded steroid receptors. GA treatment of cells altered heteroprotein complex formation with several different mutant p53 species. It increased p53 turnover and resulted in nuclear translocation of the protein in A1-5 cells. GA did not, however, appear to restore wild-type transcriptional activating activity to mutant p53 proteins in either A1-5 cells or human breast cancer cell lines.
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PMID:The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. 948 68

Apoptosis requires the activation of caspases (formerly interleukin 1beta-converting enzyme-like proteases), in particular those related to the caspase-3/7/6 subfamily. Recent data, however, revealed that, although caspase-specific inhibitors delay apoptosis, they are often incapable of preventing it. To obtain evidence for caspase-independent steps of apoptosis, we artificially created a high amount of short-lived or aberrant proteins by blocking the ubiquitin degradation pathway. A temperature-sensitive defect in the ubiquitin-activating enzyme E1 induced apoptosis independent of the activation of caspase-3 and -6 and the cleavage of their respective substrates poly(ADP-ribose) polymerase and lamin A. In addition, neither the caspase 3/7-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone were capable of blocking this type of cell death. By contrast, Bcl-2 overexpression effectively protected cells from apoptosis induced by a defect in the E1 enzyme at the nonpermissive temperature. Bcl-2 acted downstream of the accumulation of short-lived or aberrant proteins because it did not prevent the overexpression of the short-lived proteins p53, p27(kip1), and cyclins D1 and B1 under conditions of decreased ubiquitination. These results suggest the existence of short-lived proteins that may serve the role of caspase-independent effectors of apoptosis and attractive targets of the death-protective action of Bcl-2.
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PMID:Defects in the ubiquitin pathway induce caspase-independent apoptosis blocked by Bcl-2. 949 30


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