Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E6 oncoproteins encoded by the cancer-associated human papillomaviruses (HPVs) can associate with and promote the degradation of wild-type p53 in vitro. To gain further insight into this process, the ability of HPV-16 E6 to complex with and promote the degradation of mutant forms of p53 was studied. A correlation between binding and the targeted degradation of p53 was established. Mutant p53 proteins that bound HPV-16 E6 were targeted for degradation, whereas those that did not complex HPV-16 E6 were not degraded. Since the HPV-16 E6-promoted degradation involves the ubiquitin-dependent proteolysis pathway, specific mutations were made in the amino terminus of p53 to examine whether the E6 targeted degradation involved the N-end rule pathway. No requirement for destabilizing amino acids at the N terminus of p53 was found, nor was evidence found that HPV-16 E6 could provide this determinant in trans, indicating that the N-terminal rule pathway is not involved in the E6-promoted degradation of p53.
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PMID:Interaction of the human papillomavirus type 16 E6 oncoprotein with wild-type and mutant human p53 proteins. 132 Dec 90

Human papillomaviruses (HPVs) are associated with the majority of cervical cancers and encode a transforming protein, E6, that interacts with the tumor suppressor protein p53. Because E6 has p53-independent transforming activity, the yeast two-hybrid system was used to search for other E6-binding proteins. One such protein, E6BP, interacted with cancer-associated HPV E6 and with bovine papillomavirus type 1 (BPV-1) E6. The transforming activity of BPV-1 E6 mutants correlated with their E6BP-binding ability. E6BP is identical to a putative calcium-binding protein, ERC-55, that appears to be localized in the endoplasmic reticulum.
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PMID:Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. 762 74

E6-AP is a 100-kDa cellular protein that interacts with the E6 protein of the cancer-associated human papillomavirus types 16 and 18. The E6/E6-AP complex binds to and targets the p53 tumor-suppressor protein for ubiquitin-mediated proteolysis. E6-AP is an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. The amino acid sequence of E6-AP shows similarity to a number of protein sequences over an approximately 350-aa region corresponding to the carboxyl termini of both E6-AP and the E6-AP-related proteins. Of particular note is a conserved cysteine residue within the last 32-34 aa, which in E6-AP is likely to be the site of ubiquitin thioester formation. Two of the E6-AP-related proteins, a rat 100-kDa protein and a yeast 95-kDa protein (RSP5), both of previously unknown function, are shown here to form thioesters with ubiquitin. Mutation of the conserved cysteine residue of these proteins destroys their ability to accept ubiquitin. These data strongly suggest that the rat 100-kDa protein and RSP5, as well as the other E6-AP-related proteins, belong to a class of functionally related E3 ubiquitin-protein ligases, defined by a domain homologous to the E6-AP carboxyl terminus (hect domain).
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PMID:A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. 776 80

The spectrum of somatic TP53 single basepair substitutions detected in 955 cancers was compared with that of 2,224 different germline mutations in 279 different human genes (other than TP53), reported as the cause of inherited disease. This comparison reveals that, disregarding a relatively small subset (12%) of TP53 mutations that probably result from the action of exogenous mutagens, both the relative rates and the nearest-neighbor spectra of single basepair substitutions are similar in the two datasets. This spectral resemblance suggests that a substantial proportion of cancer-associated somatic TP53 mutations result from endogenous cellular mechanisms. The likelihood of clinical observation of a particular mutation type differs, however, between tumors and genetic diseases, when the chemical properties of the resulting amino acid substitutions are considered. Together with a sixfold higher observation likelihood for mutations at evolutionarily conserved residues, this finding argues that selection is a critical factor in determining which TP53 mutations are found to be associated with human cancer.
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PMID:Somatic spectrum of cancer-associated single basepair substitutions in the TP53 gene is determined mainly by endogenous mechanisms of mutation and by selection. 772 49

Despite modern therapy, one third to one half of patients who get breast cancer will eventually die from it. This disconcerting circumstance has focused attention on prevention, and preventing breast cancer will require a much better understanding of the biological abnormalities underlying its development and progression. Many studies into the mechanisms of invasive breast cancer evolution have evaluated presumed precursor lesions (e.g. proliferative disease without atypia, atypical ductal hyperplasia, and ductal carcinoma in-situ) for genetic alterations known to occur in fully developed invasive carcinomas. This approach has shed some light on events which may be important in early malignant transformation, including the observations that overexpression of the c-erbB-2 oncogene and mutations of the p53 tumor suppressor gene are present in significant subsets of DCIS, but not PDWA or ADH. Although this approach is limited by our incomplete knowledge of cancer genetics, there is still a great deal to learn about breast cancer evolution by evaluating cancer-associated genes in potential precursor lesions using established techniques such as immunohistochemistry and in situ hybridization.
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PMID:Immunohistochemical studies of early breast cancer evolution. 781 82

The E6 proteins of specific cancer-associated human papillomaviruses (HPVs) complex with and mediate degradation of the cellular anti-oncogene p53 in vitro. A critical property of p53 is its ability to stimulate transcription from promoters containing its recognition sequence. HPV E6, mutant p53 proteins, and several DNA tumor virus oncogenes inhibit the transcriptional activity of wild-type p53. In this report, the structural requirements for the interaction between HPV 16 E6 and p53 were examined both in vivo and in vitro. p53-stimulated transcription was efficiently inhibited by wild-type HPV 16 E6 and E6 mutants competent for p53 binding and degradation. A series of p53 deletions and hybrid proteins with heterologous DNA binding, dimerization and transactivation domains were analysed for transcriptional interaction with HPV 16 E6 to determine the domains of p53 required for transcriptional inhibition. These chimeric proteins were also analysed for E6 binding and E6-mediated degradation in vitro. In both assays, complex formation with E6 was mediated through the amino-terminal 345 amino acids of p53 without a specific requirement for its C-terminus. Hybrid proteins containing residues 161-345 of p53 also bound E6, but this segment of p53 was not susceptible to E6 induced proteolysis. A second region of p53, within its N-terminal 160 aa, is required for E6 induced degradation of complexed p53. Taken together, these results suggest that the complex formation between E6 and p53 is not mediated through the C-terminus of p53 and that binding and degradation are separable.
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PMID:The domain of p53 required for binding HPV 16 E6 is separable from the degradation domain. 784 70

There is accumulating evidence that the p53 protein contributes to tumor suppression by stimulating the transcription of specific cellular genes, such as the cell cycle control gene WAF1/ClP1. p53-mediated transcriptional activation is inhibited in cotransfection assays by overexpressed E6 protein from cancer-associated human papillomavirus (HPV) types, pointing at a possible molecular mechanism by which these viruses contribute to malignant cell transformation. Here we analysed the transcriptional transactivation function of endogenous p53 protein in a series of cervical cancer cell lines, which express the E6 gene from integrated viral sequences. Transient and stable transfection analyses employing p53-responsive reporter constructs indicated that HPV-positive cervical cancer cells contained transactivating p53 protein. Treatment of HPV-positive cells with genotoxic agents, such as mitomycin C, cisplatin, or u.v. irradiation, resulted in an increase of nuclear p53 protein levels and enhanced binding of p53 to a p53-recognition site. These effects were accompanied by an increase of WAF1/ClP1 mRNA levels. In several HPV-positive cell lines, these molecular events were linked to a cell cycle arrest in G1. In contrast, cancer cells containing mutant p53 genes did not contain transactivating endogenous p53 protein and lacked the p53-mediated response to DNA damaging agents. These results indicate that the tumorigenic phenotype of HPV-positive cancer cell lines does not necessarily correlate with a lack of basal or DNA damage induced p53 activities and that therefore the presence of high risk HPV sequences is not functionally equivalent to the loss of p53 function through somatic mutations of the p53 gene.
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PMID:Functional p53 protein in human papillomavirus-positive cancer cells. 789 34

Early breast neoplasia may be defined in many ways. Any non-invasive or invasive but nonmetastatic breast cancer qualifies as early neoplasia in the sense that they are non-lethal. Before we can prevent lethal breast cancer, we must gain a better understanding of the biological abnormalities underlying its development and progression. Many studies into the mechanisms of breast cancer evolution have evaluated potential precursor lesions (e.g., proliferative disease without atypia [PDWA], atypical ductal hyperplasia [ADH], and ductal carcinoma in situ [DCIS]) for genetic alterations known to occur in fully developed invasive carcinomas. This approach has shed some light on events which may be important in early malignant transformation, including the observations that overexpression of the c-erbB-2 oncogene and mutations of the p53 tumor suppressor gene are present in significant subsets of DCIS, but not PDWA or ADH. This approach is limited by our incomplete knowledge of cancer genetics. However, there is more to learn by evaluating known cancer-associated genes in potential precursor lesions using established techniques such as immunohistochemistry and in situ hybridization. Until recently, technology could not detect unknown genetic abnormalities in microscopic lesions such as PDWA, ADH, or DCIS. Now, PCR-based techniques have the theoretical ability to detect novel tumor promoter and suppressor genes in clinical samples of these very small lesions. For example, suppressor-type genes may be detected using comprehensive mapping probes to identify loss of heterozygosity in PCR-amplified DNA extracted from a few hundred cells microdissected from either fresh or archival tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biomarkers in early breast neoplasia. 800 90

Functional p53 protein is associated with the ability of cells to arrest in G1 after DNA damage. The E6 protein of cancer-associated human papillomavirus type 16 (HPV-16) binds to p53 and targets its degradation through the ubiquitin pathway. To determine whether the ability of E6 to interact with p53 leads to a disruption of cell cycle control, mutated E6 proteins were tested for p53 binding and p53 degradation targeting in vitro, the ability to reduce intracellular p53 levels in vivo, and the ability to abrogate actinomycin D-induced growth arrest in human keratinocytes. Mutations scattered throughout the amino terminus, either zinc finger or the central region but not the carboxy terminus, severely reduced the ability of E6 to interact with p53. Expression of HPV-16 E6 or mutated E6 proteins that bound and targeted p53 for degradation in vitro sharply reduced the level of intracellular p53 induced by actinomycin D in human keratinocytes. A perfect correlation between the ability of E6 proteins to reduce the level of intracellular p53 and their ability to block actinomycin D-induced cellular growth arrest was observed. These results suggest that interaction with p53 is important for the ability of HPV E6 proteins to circumvent growth arrest.
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PMID:The ability of human papillomavirus E6 proteins to target p53 for degradation in vivo correlates with their ability to abrogate actinomycin D-induced growth arrest. 805 51

Ultraviolet light has been linked with the development of human skin cancers. Such cancers often exhibit mutations in the p53 tumor suppressor gene. Ligation-mediated polymerase chain reaction was used to analyze at nucleotide resolution the repair of cyclobutane pyrimidine dimers along the p53 gene in ultraviolet-irradiated human fibroblasts. Repair rates at individual nucleotides were highly variable and sequence-dependent. Slow repair was seen at seven of eight positions frequently mutated in skin cancer, suggesting that repair efficiency may strongly contribute to the mutation spectrum in a cancer-associated gene.
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PMID:Slow repair of pyrimidine dimers at p53 mutation hotspots in skin cancer. 812 17


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