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)

The p53 gene initially was thought to be an oncogene, but recent evidence suggests that wild-type p53 can function as a tumor suppressor gene in lung, colon, and breast cancer as well as less common malignancies. This study reports the first identification of intronic point mutations as a mechanism for inactivation of the p53 tumor suppressor gene. Abnormally sized p53 mRNAs found in a small cell and a non-small cell lung cancer cell line were characterized by sequence analysis of cDNA/PCR products, the RNase protection assay and immunoprecipitation. These mRNAs were found to represent aberrant splicing leading to the production of abnormal or no p53 protein. Sequence analysis of genomic DNA revealed that a point mutation at the splice acceptor site in the third intron or the splice donor site in the seventh intron accounts for the abnormal mRNA splicing. In one patient the same intronic point mutation was found in the tumor cell line derived from a bone marrow metastasis and in multiple liver metastases but not in normal DNA, indicating that it occurred as a somatic event before the development of these metastases. These findings further support the role of inactivation of the p53 gene in the pathogenesis of lung cancer and indicate the role of intronic point mutation in this process.
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PMID:Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. 216 47

Specimens from 48 consecutive patients undergoing surgery for colorectal carcinoma and having synchronous or metachronous liver metastases (Group 1) and those from 52 consecutive patients who had no evidence of hepatic metastases within at least 5 year after colorectal resection (Group 2) were selected and compared using a multiple logistic regression analysis. A multivariate analysis using a stepwise logistic regression revealed six independent risk factors significantly related to hepatic metastases. In addition, the following logistic regression model was obtained from this analysis. P = exp a/(1 + exp a): a = 3.524(SM-V) + 2.731(Ex-V) + 2.718(E/M) + 2.562(Lo) + 1.858(p53) + 1.941(HIR) - 4.397, where P is the probability of hepatic metastasis given six independent risk factors (E/M, Ex/M ratio; Lo, location; HIR, host inflammatory cell reaction). When the estimated probability "P" in the above logistic regression model is more than 0.55 after an examination of surgical specimens, we must consider adjuvant chemotherapy and closely monitor the patient to ensure early detection of hepatic metastases.
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PMID:Risk factors related to liver metastasis in colorectal carcinoma: a multivariate analysis of clinicopathologic and immunohistochemical variables. 753 82

Using monoclonal antibody PAb 1801, p53 protein was detected in the neoplastic cells of 39 (46.9%) of 83 colorectal carcinomas studied. Patients with p53+ tumors showed a higher incidence of lymph node and liver metastases (p = 0.035); in patients whose tumors were located in the rectosigmoid, p53 expression also correlated with a more advanced stage according to Dukes' classification (p = 0.015) as well as nodal (p = 0.006) and liver (p = 0.019) metastases. Following amplification of exons 5 to 8 of the p53 gene by means of the polymerase chain reaction technique, single-strand conformation polymorphism analysis disclosed an anomalous migration pattern in 23 of the 39 p53+ tumors and in four of the 35 p53- tumors analyzed. Sequence analysis showed G:C-->A:T transitions in 63.6%, G:C-->T:A and G:C-->C:G transversions in 18.2%, deletions and insertions in 13.6%, and A:T-->G:C transitions in 4.6% of the cases. Loss of heterozygosity was studied in the DNA of 79 patients; allelic loss was found in 29 (49.1%) of the 59 informative patients. Loss of heterozygosity was correlated with p53 overexpression (p = 0.0002) as well as with the presence of mutations as detected by single strand conformation polymorphism analysis (p = 0.0024).
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PMID:Association of p53 gene and protein alterations with metastases in colorectal cancer. 769 48

To identify genetic alterations associated with acquisition of metastatic ability in colorectal carcinoma, 31 liver metastases and 40 primary tumors of colorectal carcinoma from 55 patients were analyzed for loss of chromosomal heterozygosity using 46 polymorphic DNA markers covering 15 chromosomes. Loss of heterozygosity (LOH) and/or rearrangement at the TP53 and DCC loci were detected in all liver metastases (10 of 10 at TP53 and 19 of 19 at DCC), and were observed in 59% (10 of 17) at TP53 and 75% (18 of 24) at DCC respectively in the primary tumors. Furthermore, the incidence of LOH on chromosomes 13q and 14q was higher than that on other chromosomes in liver metastasis, and it was higher in liver metastases than in primary tumors (20/30 vs. 18/39, p = 0.072 on chromosome 13q and 21/31 vs. 16/40, p = 0.018 on chromosome 14q). In 4 cases, LOH or rearrangement at loci on chromosomes 13q, 14q and 18q not detected in primary tumors was observed in liver metastases from the same patients. These results suggest that concordant p53 and DCC alterations and inactivation of several other tumor-suppressor genes, especially those on chromosomes 13q and 14q, play important roles in the acquisition of metastatic potential of colorectal carcinoma.
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PMID:Concordant p53 and DCC alterations and allelic losses on chromosomes 13q and 14q associated with liver metastases of colorectal carcinoma. 809 72

This study was designed to identify tumor suppressor genes whose inactivation is associated with the acquisition of metastatic ability in colorectal carcinoma. The results indicate that a specific subset of tumor suppressor genes is involved in metastasis of colorectal carcinoma. First, both the p53 and DCC genes were altered in 100% of liver metastases. Second, the incidence of loss of heterozygosity (LOH) at loci on chromosomes 13q, 14q, and 18q in liver metastases was higher than in primary tumors. Third, LOH or rearrangement not detected in the primary tumors was observed on chromosomes 13q, 14q and 18q in liver metastases from the same patients, while alterations on chromosome 17p were always detected in both lesions. These observations indicate that concordant inactivation of the p53 and DCC genes and inactivation of several tumor-suppressor genes, especially those on chromosomes 13q and 14q, play important roles in the acquisition of metastatic potential in colorectal carcinoma.
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PMID:[Accumulation of genetic alterations during human tumor progression]. 809 49

We examined the occurrence of apoptotic cell death in 15 advanced colorectal carcinomas with lymph-node and/or liver metastases by terminal-deoxynucleotidyl-transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL). TUNEL-positive cells were used to quantify the apoptotic index (AI: percentage of TUNEL-positive cells in carcinomatous cells). Similarly, Ki-67-positive cells were used to quantify Ki-67 labeling (KI: percentage of Ki-67-positive cells in carcinomatous cells) as a proliferative index. The mean AIs of primary colorectal carcinomas, lymph-node and liver metastases were 3.5%, 5.6% and 6.2% respectively. There was a significant group difference between primary carcinomas and lymph-node or liver metastases. The mean KIs of primary colorectal carcinomas, lymph-node and liver metastases were 51.8%, 60.1% and 61.7% respectively. There was a significant group difference between primary carcinomas and lymph-node or liver metastases. In addition, there was a close positive relationship between the AI and MI per specimen. There was no apparent correlation between AI or MI and the expression of nuclear p53 of cancer cells. These results suggested that cell proliferation and loss (apoptosis) were more frequent in metastatic foci than in primary lesions, and that apoptosis might reflect not only cell loss but also the proliferative activity of human colorectal carcinomas.
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PMID:Apoptosis occurs more frequently in metastatic foci than in primary lesions of human colorectal carcinomas: analysis by terminal-deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling. 856 13

Although intrahepatic infusion therapy with 5-fluorouracil for unresectable colorectal liver metastases may lead to improved overall survival for some patients, it is not clear why a response is not observed in others. Gene alterations in oncogenes or tumor-suppressor genes are critical events in tumor formation, and some of them could play a role in the process of drug resistance. The tumor-suppressor gene p53, which is known to trigger cell arrest or apoptosis in response to DNA damage, is found to be mutated in a wide range of human tumors. The aim of this work is to establish whether a relationship is found between p53 mutations and survival in patients undergoing adjuvant chemotherapy for advanced Dukes' D colorectal cancers. Seventeen tumors from patients treated with 5-fluorouracil regimen via intrahepatic infusion for unresectable colorectal hepatic metastasis were considered. p53 mutations from tumor DNA were detected, after amplification by PCR of exons 5 to 8, by non-radioactive single-strand conformation polymorphism and direct DNA sequencing. Patients with mutated p53 colorectal tumors had short survival, whereas prolonged survival was associated with the presence of wild-type p53 (p = 0.019). Our data suggest that mutated p53 colorectal tumors had a weak response, or even no response, to chemotherapeutic treatment. Routine assessment of p53 status would be helpful in selecting patients with only wild-type p53 gene who have a predictably better response to chemotherapy.
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PMID:p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas. 868 86

Orthotopic transplantation of human tumors in nude mice reproduces the pattern of local growth and distal dissemination. The aim of our study was to determine the pattern of genetic alterations in human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice. Eight of the sixteen orthoimplanted human pancreatic carcinomas were perpetuated through several passages. Four perpetuated tumors followed distinct patterns of distal dissemination. Point mutations in the K-ras gene, genetic aberrations in the p53 and p16 genes, and allelic losses at retinoblastoma, adenomatous polyposis coli, and deleted in colorectal cancer loci were analyzed. Perpetuated tumors maintained the pattern of genetic alterations present in primary tumors. Five perpetuated tumors contained K-ras mutations, and all tumors contained p53 and/or p16 genetic aberrations. Allelic losses were present in four of the perpetuated tumors. Additional genetic alterations were detected in 6 of 35 metastases analyzed. Five of 9 peritoneal metastases or malignant ascitic cells acquired either K-ras or second p53 mutations. In contrast, only 1 of 25 liver metastases and none of the lymph node metastases acquired additional mutations. No additional p16 gene aberrations or other allelic losses were evidenced during tumor dissemination. We conclude that orthotopically implanted pancreatic carcinomas xenografted in nude mice show a high degree of genetic stability. Mutations in K-ras and p53 genes can occur in this model system in the more advanced stages of pancreatic tumor progression, mainly during peritoneal dissemination.
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PMID:Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. 897 Nov 80

Liver metastases arise in about a third of patients with colorectal cancer. Although important clinical results have been obtained by surgical treatment in patients with limited liver involvement, other intra-arterial or systemic therapies do not provide important long term clinical benefits in patients with unresectable liver metastases. Better knowledge of the biology of liver metastases could imply a more appropriate use of the available therapeutic approaches and a retrospective definition the biologic subgroups of patients who benefit from them. Phenotypic and molecular aspects of tumor cells have been investigated and have proven to be important determinants of clinical outcome in patients with different human tumor types. Liver metastases from colorectal cancer have been scarcely studied, but cell proliferation has been shown to be a discriminant of freedom from progression and even more of long-term clinical outcome in subsets in patients treated with radical surgery. Moreover, in patients with resectable liver metastases, DNA and entity of DNA abnormalities are significantly associated with patient survival. A few recent reports have indicated a potential prognostic relevance of abnormal activation or expression of the p53 tumor suppressor gene, bel-2 protein and ras oncogene. In conclusion, prognostic biologic factors are acquiring an important role as indicators of clinical outcome in patients with liver metastases. However, all information is derived from retrospective analyses heterogeneous for patient population and biomarkers analyzed. Therefore, the comparison among results from different studies is difficult, and prospective studies are needed to develop a prognostic classification which integrates biologic and pathologic factors.
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PMID:Biological prospectives to define prognosis and treatment strategies in liver metastases from colorectal cancer. 912 89

Transfer of the SV40 large-T (LT) oncogene into isolated human and murine intestinal epithelial cells induced alterations of the ultrastructural organization and polarization of the resulting immortalized cell lines. We now demonstrate that the functional expression of the SV40 LT antigen in Caco-2 cells did not alter phenotypic markers of differentiation, including expression of villin, sucrase-isomaltase, brush border and dome formation. As compared to parental cells, the transfected Caco-2 LT9 cells exhibited similar growth curves and no invasive properties in vitro. The major oncogenic function of the SV40 LT antigen in transfected Caco-2 cells is associated with reduced latency times necessary for the manifestation of tumors in athymic nude mice. The Caco-2 cell line contained deleted and mutant p53 alleles (stop codon in position 204) and has no detectable truncated p53 protein by Western blot. Molecular complexes between the SV40 LT antigen and the retinoblastoma-related proteins pRb1 and Rb2 were clearly identified at the different phases of the growth curve. When compared to normal human colonic crypts, Caco-2 cell differentiation is related to partial redistribution of pRb1 into hypophosphorylated, antiproliferative forms. The pRb2 protein is found elevated in a subset of human colorectal tumors and their corresponding liver metastases. We conclude that: (1) Caco-2 cells exert a dominant control against the oncogenic functions of the LT antigen; (2) loss of p53 function is not restrictive for the establishment of polarity and differentiation of the enterocyte lineage; (3) the levels and phosphorylation status of the Rb1 and Rb2 proteins may play important roles in the proliferation and differentiation of normal and neoplastic human colonic mucosa.
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PMID:Enterocyte differentiation is compatible with SV40 large T expression and loss of p53 function in human colonic Caco-2 cells. Status of the pRb1 and pRb2 tumor suppressor gene products. 913 93


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