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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 25% of all bronchogenic carcinoma and is associated with the poorest 5-year survival of all histologic types. SCLC differs in its etiologic, pathologic, biologic, and clinical features from non-SCLC, and these differences have translated to distinct approaches to its prevention and treatment. Compared with other histologic types of lung cancer, exposures to tobacco smoke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification of SCLC has been revised to include three categories: (1) small cell carcinoma, (2) mixed small cell/large cell, and (3) combined small cell carcinoma. Ultrastructurally, SCLC displays a number of neuroendocrine features in common with pulmonary neuroendocrine cells, including dense core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface antigens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor suppressor genes in SCLC have been described. Dominant proto-oncogenes that have been found to be amplified or overexpressed in SCLC include the myc family, c-myb, c-kit, c-jun, and c-src. Altered expression of two tumor suppressor genes in SCLC, p53 and the retinoblastoma gene product, has been demonstrated. Cytogenetic and molecular evidence for chromosomal loss of 3p, 5q, 9p, 11p, 13q, and 17p in SCLC has intensified the search for other tumor suppressor genes with potential import in this malignancy. Bombesin/gastrin-releasing peptide, insulin-like growth factor I, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investigation. Several mechanisms of drug resistance in SCLC have been described, including gene amplification, the recently described overexpression of multi-drug resistance-related protein (MRP), and the expression of P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive disease are equivalent to the TNM stages I through III and stage IV, respectively. Therapeutically, recent strategies have attained small improvements in survival but significant reductions in the toxicities of chemotherapeutic regimens. Presently, the overall 5-year survival for SCLC is 5% to 10%, with limited disease associated with a significantly higher survival rate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Small cell lung cancer: etiology, biology, clinical features, staging, and treatment. 839 98

This article describes cytogenetic findings in human small cell lung cancer (SCLC). Included is a summary of analyses performed by the authors on 17 tumors, each of which displayed numerous chromosomal alterations. Many of the recurrent changes involve losses at the locations of tumor suppressor genes, whose loss and/or inactivation may play a crucial role in tumorigenesis. Deletions of the short arm of chromosome 3 (particularly 3p21-25) were found in every case, providing additional evidence in support of the notion that this region harbors a tumor suppressor gene(s) critical in the pathogenesis of SCLC. Cytogenetic losses of 5q21, 13q14, and 17p13 (sites of the APC, RB1, and TP53 suppressor loci, respectively) also are common in SCLC. Double minutes are found in a minority of these tumors and are associated with oncogene amplification. The genetic complexity in SCLC underscores the need for greater preventive measures and early detection.
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PMID:Molecular implications of recurrent cytogenetic alterations in human small cell lung cancer. 840 11

A polymorphism in intron 2 of the p53 gene, which gives rise to 2 alleles, A1 and A2, was analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct DNA-sequencing techniques. The distribution of this allele in the peripheral blood in the Chinese population comprising 27 healthy individuals, 30 bronchiectasis patients, 34 non-small-cell lung cancer (NSCLC) patients and 27 SCLC patients was analyzed. The genotypic distributions for this marker were significantly different between the blood of healthy individuals and SCLC patients. There was no significant difference between genotypes of Caucasians and Chinese. Tumors, normal lungs and peripheral blood of 83 adenocarcinoma and 10 squamous cell carcinoma patients were also studied. There was a significant difference in the distribution of the genotypes detected in tumor tissues vs. blood of adenocarcinoma patients. The frequency of detection of the A1/A1 genotype in the tumor tissues was increased in adenocarcinoma patients as compared with the blood of adenocarcinoma patients and was decreased in the blood of SCLC patients as compared with the blood of healthy individuals. Survival rates in Hong Kong adenocarcinoma patients with the A1/A1 genotype were lower than those in patients with A1/A2 and A2/A2 genotypes up to 30 months post-operation. Point mutations were detected at the p53 intron 2 polymorphic locus in NSCLC specimens, with a mutation rate of 15.4% (8/52). All mutations were GC transversions. The significance of this instability in p53 intron 2 remains to be elucidated.
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PMID:Detection and evaluation of p53 intron 2 polymorphism in lung carcinomas in Hong Kong. 860 79

The expression of a negative regulator of the cell cycle, p21WAF1 protein, is trans-activated by wild-type p53, but not by the mutant protein. Therefore, mutations of the p53 and WAF1 genes may be complementary. We examined DNAs from 70 human primary lung (63 of NSCLC and 7 of SCLC) and 24 pancreatic cancers (19 primary cancers and 5 cell lines) for mutations of the WAF1 gene. No mutations were detected in any samples examined, regardless of the mutational state of the p53 gene. The results suggested that aberrations of the coding sequence of the WAF1 gene are not associated with carcinogenesis in lung and pancreatic cancers.
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PMID:Absence of a mutation of the p21/WAF1 gene in human lung and pancreatic cancers. 861 30

The role of oncogenes and antioncogenes in lung tumorigenesis is discussed in this review, with particular emphasis on their prognostic significance. Mutations in the ras family of oncogenes, overexpression of the myc and neu families of oncogenes, and mutations of p53, the recessive tumor suppressor gene, occur with differing frequencies in small cell lung cancer and non-small cell lung cancer, and are usually associated with a poor prognosis. Loss of heterozygosity, notably on chromosomes 3p, 5q, 9p, 13q, and 17p, is a common feature in lung carcinomas and its importance is also discussed.
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PMID:Oncogenes and antioncogenes in lung tumorigenesis. 863 91

Surgical samples from 40 cases of primary lung cancer were studied by in situ hybridization and polymerase chain reaction (PCR) to detect HPV-DNA in different types of lung cancer. In addition, PCR-RFLP was used to examine mutation of p53 exon 7. The results showed that HPV-DNA positive rate in lung cancer was 55% (22/40 cases), including SCLC (9/9 cases), squamous cell carcinomas (8/16 cases), and adenocarcinomas (5/12 cases). Amplification of p53 exon 7 was seen in 5 of 22 HPV-DNA positive cases. RFLP analysis showed that p53 exon 7 mutation was present in two cases with gene amplification. In HPV-DNA negatives there was only one case with exon 7 amplification but no mutation. SCLC and squamous carcinoma had higher HPV infection rate than other types of lung cancer. The results suggest some relation between HPV infection and p53 gene mutation.
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PMID:[Human papillomavirus infection and p53 gene mutation in primary lung cancer]. 873 7

Small cell lung cancer (SCLC) cell growth is sustained by multiple autocrine and paracrine growth loops involving neuropeptides. The bombesin family of peptides are autocrine growth factors in H345 SCLC cells and provide a paradigm for the study of growth factors and mitogenic signaling in SCLC cells. We show that bombesin (and other neuropeptides) stimulates protein tyrosine phosphorylation (particularly focal adhesion kinase) and protein tyrosine kinase (PTK) activity in intact SCLC cells. Furthermore, the broad spectrum neuropeptide receptor antagonist [D-Arg, D = Phe, D-Trp, Leu11]substance P inhibits all neuropeptide-mediated signals (including PTK activation), SCLC cell growth in vivo and in vitro, and also increases the natural rate of apoptosis seen in growing SCLC cell lines. Hence the effect of selective PTK inhibition on SCLC cell growth and apoptosis was examined. We show that selective inhibition of PTK activity, with genistein and (3,4,5-tri-hydroxyphenyl)-methylene(-propanedinitrile) tyrphostin-25 inhibits basal and neuropeptide-stimulated SCLC cell growth. Genistein and tyrphostin-25 also stimulate apoptosis in SCLC cells. Inhibition of proliferation in these cells is intimately linke to apoptosis, because these changes occurred without any effect on SCLC cell cycle kinetics, suggesting that apoptosis occurs independently of the cell cycle and that failure to progress through the cell cycle results in apoptosis. Because tyrphostin-25 fails to influence p53 or Bcl-2 expression in these cells, this mode of programmed cell death appears to be via a p53- and Bcl-2-independent mechanism. These results provide evidence that tyrosine phosphorylation is a mitogenic signal in SCLC cells and suggest that regulation of the level of protein tyrosine phosphorylation represents a critical determinant of whether SCLC cells survive and proliferate or die by apoptosis. Thus PTK inhibition may provide a novel therapeutic option in SCLC that has become resistant to conventional chemotherapeutic agents.
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PMID:Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. 879 1

A remarkable volume of novel findings on the oncogenesis of cancer has been presented during the past decade, including the recognition of tumor suppressor genes, Rb and p53. In the field of molecular biology of the lung carcinogenesis, however, the study of the molecular events occurring during the progression from premalignant changes to invasive lung cancer, has been hampered by a number of difficulties. First, lung cancer includes different phenotypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which contains three different main types: adenocarcinoma, squamous cell carcinoma and large cell carcinoma. The development of these phenotypes of lung cancer may involve different molecular mechanisms. Second, the specific familial genetic changes of lung cancer are largely unknown. Third, the early detection of lung cancer is difficult. In this article, we review recent topics in the field of molecular oncology of the lung. We will also refer to our novel detection systems for mutations in the cells in the tissue specimens. While specific oncogenesis of lung cancer phenotypes might eventually become evident, and successful gene-therapy might be carried out according to newly established molecular technology in the near future, we should attempt to evaluate the independent multi-steps of oncogenesis in each lung cancer patient.
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PMID:[Prospective views for molecular oncology of the lung]. 883 72

Although the initial chemo-radiotherapy is relatively effective, lung cancer, especially small cell lung cancer (SCLC) usually becomes resistant for the therapy and gets higher grade of the malignant phenotype. The common genetic abnormalities, such as 3p deletion and mutational inactivation of p53 and Rb gene, have been well known. However, these abnormalities seem to be involved in the development of lung cancer because they could be detected at the early stage or even in the preneoplastic lesion. By means of loss of heterozygosity (LOH), we have determined two regions which are frequently lost in advanced lung cancer, 5q21 and 5q33-35. In previous reports, the low frequency of 5q loss in lung cancer has been shown in masses obtained at early but not advanced stages. Furthermore, we have found that one SCLC case showed a 5q deletion only in metastatic site but not in the primary lesion. These findings suggest that the inactivation of putative tumor suppressor gene(s) on 5q may play an important role for the progression of lung cancer. In 5q21 area, commonly deleted region was estimated to be 3 Mb around APC gene. This region was covered with several YAC clones and some cosmid contigs were constructed from these YAC clones. Two kinds of transcriptional units have been isolated from these contigs by exon-trapping, cross-species hybridization or northern blotting, so far. Since these cDNAs do not show significant homology with any known gene, their function cannot be estimated. We are trying to isolate full length cDNAs and to determine the functional and structural abnormalities in lung cancer at present.
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PMID:[Search for the tumor-suppressor gene(s) on chromosome 5q, which may play an important role for the progression of lung cancer]. 883 1

In a search for mutations of the TP53 tumour suppressor gene in lung cancer samples from gold miners in the Witwatersrand, South Africa, using heteroduplex and single strand conformation polymorphism (SSCP) analysis, a nonsense mutation was found in exon 6, consisting of a C to T transition and resulting in chain termination of the TP53 gene. The mutation occurred in a small cell lung cancer sample and is the first reported codon 196 TP53 mutation in both radon-associated and small cell lung cancer (SCLC) material.
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PMID:A nonsense mutation (Arg-196-Term) in exon 6 of the human TP53 gene identified in small cell lung carcinoma. 891 Aug 96


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