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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

An increasing body of evidence suggests that in addition to conventional histopathologic tumor characteristics, DNA content measurements, cell kinetic data, and investigations of tumor suppressor gene expressions might be of valuable information in breast cancer patients. Against this background we investigated immunohistochemically overexpression of the interphase associated protein proliferating cell nuclear antigen (PCNA) and the mutant p53 protein in routinely paraffin-embedded surgical specimens from 180 breast cancer patients with known nuclear DNA profiles. The mean clinical follow-up was 16 years (range 13-20 years). The percentage of PCNA immunoreactive tumor cell nuclei ranged between < 5% and 60% (mean 13.59 +/- 10.85%). There was a direct association between high levels of PCNA expression (> 20%) and p53 protein overexpression (p = 0.001), high histologic tumor grade (p = 0.009), and DNA aneuploidy (p = 0.019). Mutant p53 protein overexpression was found in 44 of 180 (24%) cases and was significantly related to high histologic tumor grade (p = 0.004), DNA aneuploidy (p = 0.001), and high levels of PCNA expression (p = 0.001). Patients with highly proliferative carcinomas (> 20% PCNA expression) had a shortened distant metastases-free survival when their neoplasms overexpressed p53. In contrast, the distant metastases-free survival of patients with highly proliferative, p53-negative tumors was significantly longer (p = 0.03). Immunohistochemical p53 protein overexpression thus appears to be indicative of an increased malignant potential in breast cancer patients. Highly proliferative tumors composed of p53 immunoreactive neoplastic cells clinically seem to behave more aggressively than the highly proliferative p53-negative tumors.
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PMID:Association of immunohistochemical p53 tumor suppressor gene protein overexpression with prognosis in highly proliferative human mammary adenocarcinomas. 784 4

The wild-type (wt) p53 tumor suppressor gene is commonly inactivated in human malignancies, either by mutations or by loss of expression. An additional proposed mechanism for inactivation of wt-p53 is amplification of the murine double minute 2 (MDM2) gene and overexpression of the MDM2 protein, which binds to p53 and eliminates its tumor suppressor function. To investigate a potential role for MDM2 in the inactivation of wt-p53 in pediatric acute lymphoblastic leukemia (ALL), we examined the expression of MDM2 and p53, as well as the occurrence of p53 mutations and possible amplification of the MDM2 gene, in 19 pediatric ALL cell lines and one pediatric acute myelogenous leukemia (AML) line. Although we did not find significant amplification of the MDM2 gene in any of the leukemic lines, we detected overexpression of MDM2 in all 10 lines that expressed wt-p53. Of the 10 lines without overexpression of the MDM2 gene, six (including the AML line) did not express p53, and four expressed mutant p53 with single point mutations in exons 7 and 8. To determine whether primary leukemic cells showed a similar correlation, we analyzed the original cryopreserved leukemic bone marrow cells from seven patients from whom cell lines were established. We obtained similar results from both the primary leukemic cells and the corresponding cell lines: overexpression of MDM2 was present in primary cells that expressed wt-p53 but not in cells that lacked expression of wt-p53. These findings suggest an important role for MDM2 in the pathogenesis of pediatric ALL in which leukemic cells express wt-p53.
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PMID:Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene. 788 79

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

The tumor-suppressor gene p53 may transactivate the transcription of genes that down-regulate cellular growth-related genes and may become oncogenic as a result of the production of mutant proteins or the loss of its protein expression. This study reports that alterations of the highly conserved consensus intervening sequences at the splice junctions may lead to the inactivation of the p53 gene. Analyses with the combined polymerase chain reaction and single-strand conformational polymorphism and direct DNA sequencing of DNAs amplified by means of asymmetric polymerase chain reaction demonstrated sequence alterations at the splice junctions of introns 5 and 7 in four human hepatocellular carcinomas, with a single base substitution at the splice junction in three and a 10-bp deletion starting from the dinucleotide AG of the acceptor site of intron 5 in the fourth. Restriction fragment length polymorphism analysis disclosed allele loss in all three informative cases. The p53 mRNA concentrations were remarkably reduced or undetectable in two hepatocellular carcinomas, whereas the two tumors (cases 2 and 3) that had single base changes at the acceptor site of intron 7 had both normal and abnormally sized p53 mRNAs. Immunocytochemistry failed to detect the wild-type and mutant p53 proteins in all four tumors. Western-blot analysis disclosed an abnormal, larger p53 protein of 55 kD in the tumor of case 3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic alterations at the splice junction of p53 gene in human hepatocellular carcinoma. 790 51

The primary genetic cancer predisposing event in many Li-Fraumeni syndrome families is a germline mutation in the p53 gene. We describe an extended Li-Fraumeni family with a germline mutation in the p53 gene involving a deletion of exon 10. The mutation is a 2.35 kilobase intragenic deletion encompassing exon 10, which results in the specific loss of the entire p53 oligomerization domain. This mutation segregates with the cancer phenotype. A lymphoblastoid cell line developed from a mutation carrier shows accumulation of mutant p53 protein by immunoblotting. However, tumor tissues from two affected carriers are negative by immunohistochemical staining. A major structural alteration specifically involving the oligomerization domain of a germline p53 gene has not been previously described and occurs in a region rarely mutated in sporadic tumors. The oligomerization domain is dispensable for many wild-type p53 functions, including transactivation, sequence-specific DNA binding, and suppression of oncogenic transformation. However, the domain appears to be required for transcriptional repression, and DNA strand reassociation. The identification of this mutation in an LFS family may yield insights into the importance of the oligomerization domain for suppressor function of the p53 tumor suppressor gene.
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PMID:A germline 2.35 kb deletion of p53 genomic DNA creating a specific loss of the oligomerization domain inherited in a Li-Fraumeni syndrome family. 793 51

Mutant tumor-suppressor gene p53 is reported in over 50% of hepatocellular carcinomas (HCC). We studied 60 HCC, 30 with large cell liver cell dysplasia (LCD), suggested to be a preneoplastic change progressing to HCC, in the adjacent non-neoplastic liver. Immunohistochemistry was performed for the presence of mutant p53 and hepatitis B surface (HBs) and core (HBc) antigens, using a labeled streptavidin-biotin technique with monoclonal (1/20) and polyclonal (1/40) anti-p53 and with anti-HBs (prediluted) and anti-HBc (1/400). Twenty-nine (48%) HCC were p53 immunopositive, with both antibodies in 9, 17 with monoclonal p53 only, and 3 with polyclonal p53 only. p53 immunoreactivity was present in 3 of 19 (16%) non-neoplastic livers, 4 of 20 (20%) cirrhotic livers, and one of 30 (3%) LCD. HBs and HBc, respectively, were present in 0% and 5% non-neoplastic livers, 20% and 10% cirrhotic livers, 7% and 10% LCD, and 3% and 5% HCC. None of the p53-positive HCC had HBV markers in adjacent liver. This frequency (48%) of p53 in HCC is similar to that in other countries. The data suggest a role for p53 mutations in hepatocarcinogenesis, even in the absence of HBV infection, apparently not progressing through LCD but occurring as a late event.
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PMID:Immunohistochemical p53 in hepatocellular carcinoma and liver cell dysplasia. 793 18

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. A considerable number of environmentally induced, cancer-related p53 mutations in human tumors have been found in a highly conserved proline-rich sequence of the p53 protein encompassed by amino acid residues 147-158. Using conformational energy analysis based on ECEPP (Empirical Conformational Energy for Peptides Program), we have determined the low-energy three-dimensional structures for this dodecapeptide sequence for the human wild-type p53 protein and three environmentally induced, cancer-related mutant p53 proteins with His-151, Ser-152, and Val-154, respectively. The results suggest that the wild-type sequence adopts a well-defined low-energy conformation and that the mutant peptides adopt well-defined conformations that are distinctly different from the conformation of the wild-type peptide. These results are consistent with experimental conformational studies demonstrating altered detectability of antigenic epitopes in wild-type and mutant p53 proteins. These results suggest that the oncogenic effects of these environmentally induced, cancer-related, mutant p53 proteins may be mediated by distinct local conformational changes in the protein.
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PMID:Conformational effects of environmentally induced, cancer-related mutations in the p53 protein. 793 52

Dominant oncogenic sequences have been shown to modulate the intrinsic radiation sensitivity of cells of both human and murine tumor cell lines. Whether transfection with candidate tumor-suppressor genes can modulate intrinsic radiation sensitivity is unknown. The data presented here demonstrate that transfection of rat embryo cells with a mutant p53 allele can increase the intrinsic radiation resistance of cells in vitro. First, transfection with mutant p53 resulted in transformed cellular morphology. Second, the transfected clone and the corresponding pooled population of transfected clones were more resistant to ionizing radiation in vitro. Last, analyses of the parameters of cell kinetics suggested that the radiobiological effects were unlikely to be due to altered parameters of cell kinetics at the time of irradiation, suggesting that mutant p53 altered the intrinsic radiation resistance of transfected cells by a more direct mechanism. Further experimentation will be necessary to develop a mechanistic approach for the study of these alterations.
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PMID:Transfection of rat embryo cells with mutant p53 increases the intrinsic radiation resistance. 793 66

One common step in the malignant progression of a wide variety of human cancers seems to be inactivation of the p53 gene, via point mutation or deletion or both; or overexpression of mutated protein with dominant transforming activity. This study shows a suppressive effect of wild type p53 on the growth of human breast cancer cells. Introduction of wild type p53 versus mutant into five human breast cancer cell lines containing mutant p53 resulted in a marked reduction in colony formation. Two of these were transfected with human wt p53 expression vectors and the other three were infected with retroviruses packaging human wt p53, both showing similar reduction in the number of surviving colonies, suggesting a role for wt p53 in suppression of breast cancer cell growth. Direct evidence for growth suppression was obtained by introduction of the temperature sensitive p53Val135 into Hs578T human breast cancer cells containing a mutant p53. This murine mutant allele p53Val135 functions as an oncogene at 37 degrees C as a tumor suppressor at 32 degrees C. The cell line generated was strongly growth inhibited at the restrictive temperature (31.5 degrees C), at which temperature the suppressor form is expressed. This inhibition of proliferation was reversible upon a temperature upshift. Analysis of the cell cycle distribution shows these growth suppressed cells to be inhibited in the G1 phase of the cell cycle. Thus wt p53 may have an important role in breast cancer tumorigenesis.
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PMID:p53Val135 temperature sensitive mutant suppresses growth of human breast cancer cells. 794 16


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