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)

Ubiquitin-conjugating enzymes (E2s) are essential components of the post-translational protein ubiquitination pathway, mediating the transfer of activated ubiquitin to substrate proteins. We have identified a human gene, UBE2L3, localized on Chromosome (Chr) 22q11. 2-13.1, encoding an E2 almost identical to that encoded by the recently described human L-UBC (UBE2L1) gene present on Chr 14q24.3. Using chromosome-specific vectorette PCR, we have determined the intron/exon structure of UBE2L3. In contrast to the intronless UBE2L1 gene, the coding sequence of UBE2L3 is interrupted by three large introns. UBE2L3-derived mRNA appears to be the predominant species in most tissues rather than the transcript from UBE2L1 or another homologous gene UBE2L2, which maps to Chr 12q12. We also present additional evidence that these genes are members of a larger multigene family. The primary sequence of the protein encoded by UBE2L3 is identical to partial peptide sequence derived from the rabbit E2 'E2-F1,' suggesting that we have identified the human homolog of this protein. This latter E2 has been demonstrated to participate in transcription factor NF-kappaB maturation, c-fos degradation, and human papilloma virus-mediated p53 degradation in vitro.
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PMID:Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3. 867 31

Inactivation of the wild type p53 protein through complexing of protein synthesized by specific subtypes of human papilloma virus (HPV) or mutation in the p53 gene in considered to play an important role in cervical carcinogenesis. The association between p53 overexpression and the presence of HPV 16 and 18 DNA was assessed in 29 cervical carcinomas, 15 carcinomas of the lower uterine segment and 30 endometrial carcinomas. In 29 cervical carcinomas (21 adenocarcinomas and 8 adenosquamous carcinomas), 7 cases were positive for HPV 16 DNA while 5 were positive for HPV 18 DNA. Nine cases (31%) showed p53 overexpression. An inverse association was seen between the presence of HPV DNA and the p53 overexpression. In 15 carcinomas of the lower uterine segment, one case was positive for HPV 16 DNA while 2 were positive for HPV 18 DNA. Overexpression of p53 was seen in 8 (53%) carcinomas of the lower uterine segment. Two of 3 HPV DNA positive carcinomas of the lower uterine segment revealed p53 overexpression. HPV DNA was not detected in endometrial carcinomas and p53 overexpression was shown in 12 (40%) cases. The association between HPV DNA and p53 overexpression differs among the tumors arising in the cervix, lower uterine segment and endometrium.
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PMID:Human papilloma virus and P53 overexpression in carcinomas of the uterine cervix, lower uterine segment and endometrium. 871 66

The role of p53, retinoblastoma (RB) and c-erbB-2 gene proteins in the pathogenesis of anal carcinomas has been examined. A total of 97 patients were included in the study. c-erbB-2, RB and p53 proteins were abnormal in 0, 5 and 34% of the cases, respectively. No correlation was observed between p53 and age, sex, tumour stage, histopathological tumour grading, human papilloma virus (HPV) affection or prognosis. It is concluded that the c-erbB-2 gene is not involved in the development of anal carcinomas; the role of the RB gene is somewhat uncertain, while p53 may be involved in about 1/3 of the cases. However, p53 is not correlated with HPV infection or clinical or histopathological data.
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PMID:Anal carcinoma: a clinical approach to p53 and RB gene proteins. 878 70

Suppression of wild-type p53 expression has been shown to enhance the radiation resistance of human diploid fibroblasts, but results concerning the role of p53 expression in the sensitivity of human tumour cells have been conflicting. In order to address this question, we transfected four human tumour cell lines with the human papilloma virus 16 E6 gene and compared the radiosensitivity of subclones expressing E6 with that of subclones transfected with the neo gene alone. E6 binds to wild-type p53 promoting its degradation and abrogating its function. Two of these cell lines, one derived from a squamous cell carcinoma and the other an osteogenic sarcoma, expressed wild-type p53. The other two cell lines were of similar origins and histologies but expressed mutant or no p53 (null). Insertion of E6 into the cell was accomplished by two techniques: (1) to-transfection of plasmid vectors containing neo and E6; (2) infection with a retroviral vector containing neo and E6. Multiple transfected subclones were examined for each cell line. Transfection with E6 and abrogation of p53 function had no significant influence on the radiosensitivity of any of the cell lines tested. In particular, there was no evidence that loss of wild-type p53 function increased the resistance of these human tumour cell lines to ionizing radiation.
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PMID:Abrogation of P53 function by transfection of HPV16 E6 gene does not enhance resistance of human tumour cells to ionizing radiation. 879 44

Normal human cells in culture become senescent after a limited number of population doublings. Senescent cells display characteristic changes in gene expression, among which is a repression of the ability to induce the c-fos gene. We have proposed a two-stage model for cellular senescence in which the mortality stage 1 (M1) mechanism can be overcome by agents that bind both the product of the retinoblastoma susceptibility gene (pRB)-like pocket proteins and p53. In this study we determined whether the repression of c-fos at M1 was downstream of the p53 or pRB-like "arms" of the M1 mechanism. We examined c-fos expression during the entire lifespan of normal human fibroblasts carrying E6 (which binds p53), E7 (which binds pRB), or both E6 and E7 of human papilloma virus type 16. The results indicate a dramatic change in cellular physiology at M1. Before M1, c-fos inducibility is controlled by an E6-independent mechanism that is blocked by E7. After M1, c-fos inducibility becomes dependent on E6 whereas E7 has no effect. In addition, a novel oscillation of c-fos expression with an approximately 2-h periodicity appears in E6-expressing fibroblasts post-M1. Accompanying this shift at M1 is a dramatic change in the ability to divide in low serum. Before M1, E6-expressing fibroblasts growth arrest in 0.3% serum, although they continue dividing under those conditions post-M1. These results demonstrate the unique physiology of fibroblasts during the extended lifespan between M1 and M2 and suggest that p53 might participate in the process that represses the c-fos gene at the onset of cellular senescence.
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PMID:Age-dependent alterations of c-fos and growth regulation in human fibroblasts expressing the HPV16 E6 protein. 881 2

Okadaic acid (OA) is a serine/threonine protein phosphatase inhibitor and has been shown to induce apoptosis in a number of different tumor cell lines, including human breast carcinoma (HBC) cells. The molecular basis of OA-induced apoptosis remains to be investigated. Here, we demonstrate that the OA concentration that inhibits only protein phosphatase 1 and 2A was sufficient to induce apoptosis in HBC cells. In MCF-7 cells, the OA-induced apoptosis was coupled with the overexpression of endogenous p53, p21Waf1/Cip1, and Bax proteins, whereas the Rb protein levels were decreased. OA also induced apoptosis and concomitantly enhanced the p21Waf1/Cip1 and Bex levels in human papilloma virus protein E6-transfected variants of MCF-7 cells, in which p53 function had been disrupted. OA, by contrast, had no effect on the levels or the subcellular localization of Gadd45 and Bcl2 proteins in either wild-type of E6-transfected MCF-7 cells. Bcl-xL, Bcl-xS, and Bak levels were also unchanged after OA treatment in both cell types. OA-induced apoptosis and its effect on the expression of the above molecular markers occurred in the absence of any detectable changes in the cell cycle phase distribution. On the basis of our findings, we conclude the following: (a) OA-induced apoptosis in HBC cells occurs independently of cell cycle arrest; (b) the wild-type p53 function is not an absolute prerequisite for OA-induced cell death; and (c) OA-induced apoptosis is associated with up-regulation of endogenous p21Waf1/Cip1 and Bax protein levels.
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PMID:Cell cycle-independent regulation of p21Waf1/Cip1 and retinoblastoma protein during okadaic acid-induced apoptosis is coupled with induction of Bax protein in human breast carcinoma cells. 895 27

We have shown previously that p53(-/-) fibroblasts show greater sensitization by caffeine to the lethal effects of ionizing radiation compared with p53(+/+) cells. Recently published data have suggested a possible role of p53 in nucleotide excision repair: an association of p53 and xeroderma pigmentosum group B protein and a greater sensitivity to cisplatin of RKO cells transfected with the E6 protein of human papilloma virus (inactivating p53). We show that p53(+/+) and p53(-/-) cells have equal sensitivity to germicidal UV light (as with ionizing radiation). However, the introduction of 2 mM caffeine led to a sensitization enhancement ratio (at 10% survival) of 1.8 in p53(-/-) cells, but only 1.3 in wild-type (p53+/+) cells. Lower doses of caffeine had less effect, and 0.1 mM caffeine resulted in no detectable sensitization of either cell type to UV light in contrast to X-rays. The differential sensitivity of p53(-/-) cells to X-rays and caffeine was thought to be due to override of the G2-M block to cell cycle progression. In response to UV light, cells accumulate in S phase, and the magnitude of S-phase accumulation was observed to be greater in p53(-/-) cells. Caffeine had little effect on the cell cycle distribution in p53(+/+) cells. However, for p53(-/-) cells, a greater proportion were in S phase after treatment with caffeine, and a complete loss of S-phase delay was observed after UV irradiation. In conclusion, the role of p53 in nucleotide excision repair appears to be of little significance for cell survival. Greater sensitization of p53(-/-) cells to caffeine could be mediated via override of S-phase delay.
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PMID:p53-null cells are more sensitive to ultraviolet light only in the presence of caffeine. 939 72

Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory proteins. This pathway leads to the covalent attachment of one or more multiubiquitin chains to target substrates which are then degraded by the 26S multicatalytic proteasome complex. Multiple classes of regulatory enzymes have been identified that mediate either ubiquitin conjugation or ubiquitin deconjugation from target substrates. Timed destruction of cellular regulators by the ubiquitin-proteasome pathway plays a critical role in ensuring normal cellular processes. This review provides multiple examples of key growth regulatory proteins whose levels are regulated by ubiquitin-mediated proteolysis. Pharmacological intervention which alters the half-lives of these cellular proteins may have wide therapeutic potential. Specifically, prevention of p53 ubiquitination (and subsequent degradation) in human papilloma virus positive tumors, and perhaps all tumors retaining wild-type p53 but lacking the retinoblastoma gene function, should lead to programmed cell death. Specific inhibitors of p27 and cyclin B ubiquitination are predicted to be potent antiproliferative agents. Inhibitors of IkappaB ubiquitination should prevent NFkappaB activation and may have utility in a variety of autoimmune and inflammatory conditions. Finally, we present a case for deubiquitination enzymes as novel, potential drug targets.
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PMID:The ubiquitin-mediated proteolytic pathway as a therapeutic area. 902 Mar 79

Overexpression of the tumour suppressor gene product p53 is common in oesophageal adenocarcinoma. This may be due to gene mutation, but overexpression can also result from complexing between viral proteins and p53; a number of viruses are causally linked with malignancy. This study therefore investigated the prevalence in oesophageal adenocarcinoma of viruses whose gene products are capable of interacting with p53. Seventeen tumours and 17 normal oesophagi were screened for specific DNA sequences from human papilloma virus (HPV), Adenovirus type 12, Epstein-Barr Virus (EBV), and cytomegalovirus (CMV). Frozen sections were analysed by polymerase chain reaction, and results were confirmed by Southern blot hybridization. Overexpression of p53 was studied immunohistochemically. Overexpression of p53 was identified in 11 of 17 tumours. No viral sequences were detected for HPV, CMV, or Adenovirus in any tumour. EBV sequences were found in eight of 17 tumours, and eight of 17 negative controls. There is therefore no evidence of HPV 16, 18 and 33, Adenovirus 12 or CMV infection in oesophageal adenocarcinoma. EBV infection in the oesophagus is of doubtful significance, in view of the high incidence in the control population. Overexpression of p53 cannot be explained by complexing with common viral proteins, and must be related to other intracellular mechanisms.
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PMID:Investigation of oesophageal adenocarcinoma for viral genomic sequences. 906 43

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


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