Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. The morphological changes progress from hyperplasia, to metaplasia, to dysplasia, to carcinoma in situ, to invasive cancer and finally to metastatic cancer. Multiple molecular changes have been documented in lung cancers, both small cell (SCLC) and non-small cell (NSCLC) types. The number of changes has been estimated to be in double digits. These changes include activation of dominant oncogenes myc family, (K-ras and neu genes), as well as loss of recessive growth regulatory genes or anti-oncogenes (p53, and RB as well as unidentified gene or genes on chromosome 3). However, cytogenetic and molecular genetic studies indicate that multiple other specific sites of actual or potential DNA loss may be present in lung cancers. Other changes may include development of drug resistance, and production of growth factors and their receptors. It is tempting to associate specific molecular changes with specific morphological changes, as has been attempted in the colon. However, because of the difficulties in serially sampling the respiratory tract, such studies have not been performed to date. Documentation of molecular changes in premalignant lesions and prospective studies of their prognostic effects will be necessary for the design of rational chemoprevention trials.
 ...
PMID:The molecular biology of lung cancer. 130 9

The p53 gene has been implicated as a tumor suppressor gene involved in the pathogenesis of lung cancer. Our previous study revealed that the p53 gene is frequently mutated with a distinct nucleotide substitution pattern in small cell lung cancer specimens in Japanese patients. In this study, we examined 30 primary, resected non-small cell lung cancer samples in Japanese patients using complementary DNA-polymerase chain reaction and sequencing. Mutations changing the p53 coding sequence were found in 14 of 30 tumor samples (47%), while G:C to T:A transversions which are uncommon in other cancers such as colon cancer were the most frequently observed mutations, in agreement with an earlier report on non-small cell lung cancer in American patients. Furthermore, the present study shows for the first time that in univariate and multivariate analyses, the presence of p53 mutations is closely associated with lifetime cigarette consumption.
 ...
PMID:p53 mutations in non-small cell lung cancer in Japan: association between mutations and smoking. 131 70

Mutation of one p53 allele and loss of the normal p53 allele [loss of heterozygosity (LOH)] occur in many tumors including lung cancers. These alterations apparently contribute to development of cancer by interfering with the tumor suppressor activity of p53. We directly sequenced amplified DNA in the mutational hot spots (exons 4-8) of p53 in DNA samples from 40 lung cancers. Most (31 of 40) samples were preselected for LOH in the region of p53. We detected 23 p53 mutations within these exons in 22 lung cancers; no p53 mutations were found in normal tissue of the patients. One-half of the mutations were G to T transversions on the nontranscribed strand, consistent with mutagenesis by tobacco smoke. Mutations of C to A on the nontranscribed strand, which would result from G to T mutations on the transcribed strand, were detected only in one sample. Three of 23 mutations were nonsense mutations; to date, nonsense mutations of p53 have not been reported in lung cancer. Mutation of this p53-coding region was detected in 20 of 27 small cell lung cancer samples, representing a 70% occurrence. Mutation of the p53 gene is apparently very frequent in small cell lung cancers. When LOH in the p53 region could be determined, complete concordance occurred between a sample having both a p53 mutation and LOH in the region of p53 (18 of 18 samples). Twelve samples of lung cancer had LOH in the region of p53, but the samples had no detectable p53 mutations, suggesting either alterations outside the known mutational hot spots of p53 or alterations of another unidentified tumor suppressor gene in the region of p53.
 ...
PMID:p53 mutations in human lung tumors. 131 96

Using immunoblotting techniques we studied the sera from small cell lung cancer and non-small cell lung cancer patients for antibodies directed against p53. We have also characterized the majority of these patients' tumors for p53 mutations. In the sera of 13% of the patients (4 of 40 small cell lung cancer and 2 of 6 non-small cell lung cancer) we found antibodies specific for the p53 tumor suppressor gene product. All of the antibody-positive patients tested had p53 missense mutations and expressed detectable p53 antigen in their tumor cell lines. No anti-p53 antibodies were detected in sera from patients whose tumor had p53 stop, splice/stop, splice, or frameshift mutations (n = 10). Thus, while we find that the ability of lung cancer patients to develop anti-p53 antibodies is correlated with the type of p53 mutation, many patients have tumors with missense p53 mutations and did not develop anti-p53 antibodies. The presence of p53 antibodies was not correlated to stage, prior treatment, sex, or survival. None of these lung cancer patient sera had measurable amounts of p53 antigen. By immunoblotting all six anti-p53 antisera we were able to detect a variety of mutant p53 proteins (including those from antibody-negative patients) and detected wild-type p53 protein. The development of anti-p53 antibodies represents an interesting model system for studying immune responses in cancer patients against mutant oncogene products.
 ...
PMID:Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation. 132 37

Deletions of the 3p chromosome region and molecular alterations of the tumor suppressor genes RB1 and TP53, located, respectively, at 13q14 and 17p13, are well-documented in small cell lung cancer (SCLC). Because of technical difficulties, karyotypes of primary SCLC specimens are rarely reported. In this study, detailed cytogenetic analysis was performed on 13 early passage SCLC cell lines and fresh specimens, including 4 lung primaries. Numerous chromosome alterations were found, even in newly diagnosed primary tumors. Consistent with previous molecular studies, chromosomal losses of 3p (13 cases) and 17p13 (12 cases) were frequently observed. Numerical losses of chromosome 13 and structural rearrangements affecting 13q14 were identified in 10 specimens. In addition, losses of chromosome 5 and structural alterations of 5q occurred in 12 tumors; among these, 9 displayed losses of region 5q13-q21. Double minutes were found in 4 cases (3 of 5 specimens from patients who received prior cytotoxic therapy but only 1 of 8 from untreated patients). DNA analysis revealed amplification of either MYC1 or MYCN in cells from each of these 4 tumors. Overall, the cytogenetic findings underscore that progression of SCLC involves multiple genetic changes and suggest further that a tumor suppressor gene(s) on 5q may contribute to SCLC tumorigenesis.
 ...
PMID:Chromosome alterations in human small cell lung cancer: frequent involvement of 5q. 134 89

Typical carcinoid, atypical carcinoid, and small cell lung cancer (SCLC) fall within the spectrum of neuroendocrine lung neoplasms. This paper investigates the immunohistochemical expression of the products of tumour suppressor genes p53 and retinoblastoma (RB), together with proliferation (PCNA and Ki67) and neuroendocrine differentiation markers, in 14 typical carcinoids, ten atypical carcinoids, four borderline atypical carcinoid/SCLC, and 11 SCLC. We demonstrated that the phosphoprotein p53 and RB product can be immunolocalized on routine histological material. p53 protein was absent in all typical and atypical carcinoids, while it was abnormally expressed in eight SCLC and one borderline case. RB product was detected in all typical carcinoids and in two atypical carcinoids, while it was consistently absent in the other cases. PCNA-labelled cells were less than 4 per cent in typical carcinoids, about 40 per cent in atypical carcinoids, and over 70 per cent in SCLC. PCNA labelling index discriminates between typical and atypical carcinoids. Neuroendocrine differentiation was evaluated by a semi-quantitative method: a mean score value was obtained, which was high in typical carcinoids, intermediate in atypical carcinoids, and low in SCLC. Our data was obtained, which was high in typical carcinoids, intermediate in atypical carcinoids, and low in SCLC. Our data show that the decrease in neuroendocrine features from typical carcinoid to SCLC is paralleled by an increase in proliferative activity and by an altered expression of tumour suppressor gene products. The above findings have diagnostic relevance.
 ...
PMID:Tumour suppressor gene products, proliferation, and differentiation markers in lung neuroendocrine neoplasms. 135 31

Recent studies have suggested that the p53 oncoprotein might function normally as a tumor suppressor. Mutations in highly conserved regions of the p53 gene have been observed in numerous types of tumors and tumor cell lines. To detect in a more sensitive manner p53 gene mutations in small cell lung cancer (SCLC) we utilized the single strand conformation polymorphism (SSCP) technique of Orita et al., (1989). Using PCR primers for the most highly conserved regions of the p53 gene, including exons 4-9, we have identified p53 mutations in 5 of 9 small cell lung cancer (SCLC) tumor DNA samples and in 1 SCLC cell line. None of the mutations seen in tumor DNA samples were present in normal DNA from the same patients, indicating that mutation of the p53 gene in these tumors was a somatic event. Of the six mutations observed, two were found in exon 7, three were found in the region encompassing exons 8 and 9, and one was found in the region encompassing exons 5 and 6. Nucleotide sequencing of one of the exon 7 mutations and one of the exon 8-9 mutations indicated that each was a C to T transition. In SCLC-6 the mutation resulted in substitution of serine for proline at amino acid 278 and in SCLC-4 substitution of tryptophan for arginine at amino acid 248, both nonconservative amino acid substitutions. Both of these changes are in regions of the p53 gene where mutations have been observed in other tumors. Two additional mutations were observed in SCLC cell lines using conventional PCR techniques. One of these is a mutation which results in altered splicing of the p53 pre-mRNA.
 ...
PMID:Use of the single strand conformation polymorphism technique and PCR to detect p53 gene mutations in small cell lung cancer. 164 2

The p53 gene has been implicated as a tumor-suppressor gene whose disruption is involved in the pathogenesis of common human cancers. The results of extensive analysis of p53 mutations in non-small cell lung cancers (NSCLCs) have revealed that p53 is mutated in 45% of NSCLC with base changes different from those of colon cancer. In this study, we examined 17 SCLC tumor samples taken directly from 15 patients as well as the corresponding nine tumor cell lines. Mutations changing the p53 coding sequence were found in 11 of 15 patients (73.3%) and showed a similar but distinct nucleotide substitution pattern compared with NSCLC, suggesting that a different mutagenic process is involved. In addition, a strong correlation was seen between the presence of p53 mutations in tumors and the successful establishment of the corresponding cell lines, suggesting that p53 mutations can confer a selective growth advantage in vitro (and probably also in vivo).
 ...
PMID:The p53 gene is very frequently mutated in small-cell lung cancer with a distinct nucleotide substitution pattern. 165 62

Molecular and cell biologic studies of a large number of lung cancer cell lines of all histologic types have revealed several mechanisms active in the pathogenesis of these cells. Small cell lung cancer (also called "oat cell" lung cancer) has a deletion involving chromosome region 3p(14-23) that is confirmed by DNA restriction fragment length polymorphisms analysis (studies done in collaboration with Dr. Susan Naylor). Several lung cancers of both small cell and non-small cell type (including adeno- and squamous cell lung cancer) express the proto-oncogenes c-, N-, or L-myc, and in some cases more than one of these family members. N-myc appears restricted in its expression to the small cell lung cancer type while c-myc and L-myc can be expressed in both small cell and non-small cell lung cancers. Many lung cancers of all histologic types also express large amounts of p53, which are not correlated with the amount or type of myc gene product expressed. In small cell lung cancer, high levels of myc gene expression are usually associated with gene amplification, and not uncommonly there is rearrangement of some of the amplified copies. In non-small cell lung cancer, expression without amplification or rearrangement of myc genes is seen. In contrast, high level expression of p53 is not associated with gene amplification in any lung cancer type. In addition, to these proto-oncogenes acting at a presumed nuclear locus, there is increased expression of various ras family members and the c-raf-1 proto-oncogene (in collaboration with Dr. Ulf Rapp). Lung cancer cells in tissue culture can grow in medium without serum and few or no other growth factors added. Thus, it appears that lung cancer cells can produce their own growth factors which can act in an "autocrine" fashion. The best characterized example of this is gastrin releasing peptide (GRP, also called bombesin) produced by small cell lung cancer. In at least some small cell lung cancers, interference with GRP action by specific monoclonal antibodies results in inhibition of tumor cell growth in culture and in nude mouse xenografts. Thus, constitutively expressed GRP gene may function as a cellular oncogene under certain circumstances in small cell lung cancer. Based on these observations we are proposing to test monoclonal anti-GRP antibodies in patients.
 ...
PMID:Chromosomal deletion, gene amplification, alternative processing, and autocrine growth factor production in the pathogenesis of human lung cancer. 333 4

Within the past few years, the measurement of serum and tissue markers has had an increasing influence on clinical decisions about initial treatment and follow-up. Lung cancer illustrates the types and importance of these various markers. This review presents data concerning the most studied and interesting markers in non-small cell (NSCLC) and small cell lung cancer (SCLC). CEA, TPA, SCC-Ag, CYFRA 21-1, ferritin, CA19-9, CA50, CA242, H-K-N-ras mutations and p53 mutation seem to be the most prolific in NSCLC, while NSE, BN/GRP, CK-BB, NCAM, IL-2R, IGF-I, transferrin, ANP, mAb (cluster 5), Le-y and c-N-L-myc mutation are markers in SCLC patients. Some of these serum markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure to allow change of the regimen. The study of these markers also may lead to a better understanding of the biological characteristics of lung cancer. The information derived from these biological studies represents the most promising avenue towards new treatment strategies, as well as attempts at secondary prevention.
 ...
PMID:Clinical tumour markers in lung cancer. 753 17


1 2 3 4 5 6 7 8 9 10 Next >>