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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of human wild type and mutant p53 proteins on the human multidrug resistance (MDR1) promoter was studied in a p53-negative human cell line. Transient expression of MDR1 promoter-chloramphenicol acetyltransferase reporter gene constructs (MDRCAT) cotransfected with p53 expression vectors was analyzed in H358 lung carcinoma cells. Cotransfection with a wild type p53 expression vector stimulated MDRCAT activity, while cotransfection with mutant p53 expression vectors altered at amino acid positions 181, 252, 258, or 273 failed to stimulate expression. Wild type p53 stimulation of MDRCAT activity was time dependent with maximal expression occurring 24-30 h following transfection and correlating with high p53 protein levels. MDR1 promoter deletion analysis suggested that the sequences involved in wild type p53 stimulation of MDRCAT activity were contained within the region from -39 to +53 relative to the start of transcription at +1. This region contains no TATA or p53 consensus binding sequence but does contain an initiator sequence. Wild type p53 stimulation of MDRCAT expression also occurred in parental and doxorubicin-resistant SW620 colon and parental 2780 ovarian cancer cell lines, indicating that wild type p53-mediated simulation of the MDR1 promoter is not restricted to a single cell line.
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PMID:Wild type p53 stimulates expression from the human multidrug resistance promoter in a p53-negative cell line. 782 27

We have constructed recombinant human adenoviruses that express wild-type human p53 under the control of either the Ad 2 major late promoter (MLP) or the human cytomegalovirus (CMV) immediate early gene promoter. Each construct replaces the Ad 5 E1a and E1b coding sequences necessary for viral replication with the p53 cDNA and MLP or CMV promoter. These p53/Ad recombinants are able to express p53 protein in a dose-dependent manner in infected human cancer cells. Tumor suppressor activity of the expressed p53 protein was assayed by several methods. [3H]Thymidine incorporation assays showed that the recombinant adenoviruses were capable of inhibiting DNA synthesis in a p53-specific, dose-dependent fashion. Ex vivo treatment of Saos-2 tumor cells, followed by injection of the treated cells into nude mice, led to complete tumor suppression using the MLP/p53 recombinant. Following a single injection of CMV/p53 recombinant adenovirus into the peritumoral space surrounding an in vivo established tumor derived from a human small cell lung carcinoma cell line (NIH-H69), we were able to detect p53 mRNA in the tumors at 2 and 7 days post-injection. Continued treatment of established H69 tumors with MLP/p53 recombinant led to reduced tumor growth and increased survival time compared to control treated animals. These results indicate that recombinant adenoviruses expressing wild-type p53 may be useful vectors for gene therapy of human cancer.
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PMID:Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. 783 67

Overexpression of the mdm2 protooncogene protein, which can lead to the inactivation of normal p53, has been observed in some human cancers. The mdm2 gene is positively regulated by p53, providing for a feedback loop in the control of both p53 and mdm2 activity. The expression of the mdm2 and p53 proteins in different non-small cell lung carcinoma (NSCLC) cell types harboring wild-type or mutant p53, or lacking p53 altogether, were investigated to determine whether a correlation exists between the expression of these two proteins. The mdm2 protein was expressed at very low levels in all NSCLC lines examined, regardless of the p53 status. To determine whether mdm2 could be induced by p53 in NSCLC, NSCLC cells were transfected with a recombinant adenovirus expressing high levels of wild-type p53. The highest levels of exogenous wild-type p53 were observed in p53-null H358 and H1299 cells and in H226b cells expressing endogenous wild-type p53 were observed in p53-null H358 and H1299 cells and in H226b cells expressing endogenous wild-type p53. In these cells, wild-type p53 induced the expression of 90/92K M(r) mdm2 proteins, as well as several faster-migrating mdm2-related species exhibiting relative mobilities of 76/78K, 57/59K, 46K, 28K, and 12K. Northern analyses of H358 and H1299 cells transfected with wild-type p53 showed that these cells expressed three species of mdm2 mRNA of 5.5, 4.6-3.8, and 2.1 Kb in size. Subcellular fractionation revealed that the 90/92K M(r) mdm2 protein species was localized to both the crude plasma membrane/cytoplasmic and nuclear fractions, and that the smaller mdm2 proteins associated selectively with different nuclear substructures. The 76/78K, 57/59K, and 46K Mr(r) mdm2 proteins may be derived by differential splicing of the 5.5 Kb mRNA, and their differential compartmentalization within the nucleus suggests that each has a distinct function, potentially in the regulation of p53 and other gene products.
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PMID:Selective compartmentalization of different mdm2 proteins within the nucleus. 787 79

We have performed a comprehensive analysis of the DNA copy number changes that occur in 18 small cell lung carcinoma cell lines using comparative genomic hybridization (Kallioniemi et al., Science (Washington DC). 258: 818-821, 1992). DNA copy number abnormalities detected in this study include previously identified increases at 1p22-32 (L-myc), 2p24-25 (N-myc), and 8q24 (c-myc) and decreases at 17p13 (p53), 13q14 (RB), and 3p. In addition, novel DNA copy number increases were detected at 5p, 1q24, and Xq26, and novel decreases were found at 22q12.1-13.1, 10q26, and 16p11.2. Many of the most common DNA copy number changes revealed are at loci not previously recognized to be important in small cell lung cancer. In addition, a number of the DNA copy number changes, including increases at 1p22-32, 2p24-25, and 3q22-25 and a decrease on 18p, were found to occur preferentially in small cell lung carcinoma lines of the "variant" phenotype. This correlation suggests that genes may reside at these loci whose overexpression or inactivation contributes to the radiation resistance or aggressive growth phenotypes characteristic of this subtype of small cell lung carcinoma.
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PMID:Identification of frequent novel genetic alterations in small cell lung carcinoma. 792 22

Although it is widely accepted that tumor suppressor genes play an important role in the genesis and progression of human cancer, little is known about genetic events that accumulate during multistage lung carcinogenesis. Thus, to determine a subset of tumor suppressor genes that are involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), 22 brain metastases and 23 stage I primary lung tumors were examined for allelic losses at 40 loci on 10 chromosomes including the loci of 5 tumor suppressor genes, APC, WT1, RB, p53, and DCC. The incidence of allelic losses on chromosomes 3p, 13q, and 17p was high (> 60%) in both primary tumors and brain metastases. In brain metastases, a high incidence of allelic losses (> 60%) was also observed at loci on chromosomes 2q, 18q, and 22q, and the incidence of allelic losses on these chromosomes in brain metastases was significantly higher than that in primary tumors (P < 0.05). In two cases of brain metastases with corresponding primary lung tumors, sequential accumulation of allelic losses during progression of primary lung tumors was observed on several chromosomes including chromosomes 2q and 18q. These results indicate that, besides loss of heterozygosity for chromosomes 3p, 13q, and 17p, loss of heterozygosity for chromosomes 2q, 18q, and 22q also occurs frequently in advanced NSCLCS. Thus, it is possible that loss of heterozygosity on chromosomes 2q, 18q, and 22q occurs late in the progression of NSCLC and/or causes phenotypic alterations of NSCLC cells into more aggressive ones.
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PMID:Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma. 792 10

Non-small lung cancer (NSCLC) is a disease that exhibits multiple genetic lesions. Lung Cancer Study Group (LCSG) 871 was designed to analyze this group of malignancies for alterations in growth factors and/or their receptors, oncogenes, tumor suppressor genes, and immediate early transcription factor genes. Immunohistochemical analysis showed that 32% of evaluable cases studied contained absent or abnormal Rb expression. Sequence analysis of the p53 gene revealed that 58% of these cancers contained structural alterations of this gene, whereas only 45% of these cases overexpressed p53 by immunohistochemical analysis. Finally, both Northern blot and immunohistochemical analysis showed that these tumors exhibited changes in the mRNA and protein expression levels respectively of the immediate early transcription factor genes c-fos, c-jun, and EGR, in that less expression of these genes was evident in the tumors compared with adjacent normal tissue. Understanding both the biologic and molecular significance of these findings may allow us to explore novel modalities for treatment of this disease.
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PMID:Tumor suppressor and immediate early transcription factor genes in non-small cell lung cancer. 798 67

We investigated the correlation of p53 abnormalities with survival in 85 patients with non-small cell lung cancer (NSCLC) who had undergone resection with curative intent as part of Lung Cancer Study Group (LCSG) 871. Our previous studies showed that only a subset of p53 mutations in lung cancers result in overexpression. In addition, protein overexpression has been described in the absence of mutation. Therefore, we determined both p53 protein overexpression (by immunostaining) and p53 and ras gene mutations (by single-strand conformation polymorphism and DNA sequencing) in this set of resected tumor specimens. Clinical follow-up data were available for 75 cases. Of the studied patients, 64% showed p53 overexpression and 51% had mutant p53 sequences; however, the concordance rate was only 67%. There was a negative survival correlation with positive p53 immunostaining (p = 0.05), but not with the presence of gene mutations (p = 0.62) in this group of patients. Overexpression of p53 protein determined by immunostaining may contribute to adverse outcome due to the ability of p53 to act as a dominant oncogene, or alternatively, overexpression may reflect ongoing DNA damage in the tumor as a marker for a more aggressive behavior. When adjusted for stage, age, and gender by multivariate analysis, however, there was no independent impact of p53 overexpression on survival.
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PMID:p53 immunostaining positivity is associated with reduced survival and is imperfectly correlated with gene mutations in resected non-small cell lung cancer. A preliminary report of LCSG 871. 798 68

The present study examines interferon-gamma (IFN gamma)-induced changes in the expression of immunomodulatory genes, proliferation-associated genes, and squamous-specific genes in primary cultures of human bronchial epithelial cells and fibroblasts. IFN gamma induced the expression of guanylate binding protein (GBP or p67) and the MHC class II antigen, HLADR alpha, in both epithelial cells and fibroblasts. In contrast, the expression of complement component C3 was induced in bronchial epithelial cells but not in fibroblasts. Similarly, IFN gamma induced growth arrest (EC50 approximately 50 U/ml) only in bronchial epithelial cells. This growth arrest was accompanied by a down-regulation of cdc2, E2F-1, and p53 mRNA levels and was associated with expression of the squamous-specific marker genes, transglutaminase type I and cornifin. These findings are consistent with IFN gamma inducing squamous differentiation in bronchial epithelial cells. In contrast, several lung carcinoma cell lines did not respond to IFN gamma with respect to the down-regulation of proliferation-associated genes or the induction of squamous-specific genes. However, GBP expression was induced in all the cell lines in response to IFN gamma. The present study demonstrates that cultured human bronchial epithelial cells are sensitive to the immunomodulatory, growth-inhibitory, and differentiation-inducing properties of IFN gamma. In contrast, several lung carcinoma cell lines are insensitive to the growth-inhibitory and differentiation-inducing actions of IFN gamma, suggesting they may have acquired defects in certain IFN gamma signaling pathways. Although the growth of human bronchial fibroblasts is not altered, expression of certain immunomodulatory genes is induced by IFN gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential responsiveness of human bronchial epithelial cells, lung carcinoma cells, and bronchial fibroblasts to interferon-gamma in vitro. 804 75

Proliferation of five non-small cell lung carcinoma (NSCLC) cultures was inhibited after 16 h exposure to retinoic acid. We investigated whether expression of the p53 protein correlated with the growth pattern of NSCLC lines observed in the presence of retinoic acid Levels of wild-type p53 protein underwent fivefold increases in lines H460a and H226b after 16 to 48 h treatment with 5 microM retinoic acid but then decreased to undetectable amounts in these cell lines after 72 h retinoic acid treatment. Levels of p53 transcripts remained unchanged during the time of increases in protein expression in retinoic acid-treated H460a cells, suggesting that a post-translational mechanism was involved in the increased expression of the protein. Pulse-chase analysis demonstrated that wild-type p53 was significantly more stabile in H460a cells treated with retinoic acid, exhibiting a half-life greater than 6 h, in contrast to 3 h for the protein in untreated control cells. The retinoic acid-mediated effect was specific for wild-type p53, since expression of mutant p53 in the H596b and H322j cell lines remained relatively unchanged even after 72 h exposure to retinoic acid. We conclude that retinoic acid induces stabilization of wild-type p53 in NSCLC cells by a post-translational mechanism. Furthermore, increases in expression of p53 were not responsible for the retinoic acid-induced transient inhibition of growth of NSCLC cells, since the growth of H358 p53-null cells also was inhibited by retinoic acid.
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PMID:Transient stabilization of p53 in non-small cell lung carcinoma cultures arrested for growth by retinoic acid. 808 49

We describe the isolation, growth-suppressing activity, and chromosomal localization of the human homologue of the murine growth-arrest-specific gene gas1. Overexpression of h-gas1 is able to block cell proliferation in the A549 lung carcinoma and the T24 bladder carcinoma cell lines. No effect was observed when h-gas1 was introduced into the osteosarcoma cell line SAOS-2 and into the adenovirus-type-5 transformed cell line 293. This finding is related to our previous evidence that simian virus 40-transformed NIH 3T3 cells are also refractory to murine gas1 overexpression, suggesting that the retinoblastoma and/or p53 gene products have an active role in mediating the growth-suppressing effect of gas1. We also show that h-gas1 is on chromosome 9q21.3-22.1, in a region considered to be a fragile site. Altogether, the results raise the possibility that h-gas1 may be a target for genetic alterations leading to its inactivation in tumor cells.
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PMID:Structure, function, and chromosome mapping of the growth-suppressing human homologue of the murine gas1 gene. 812 93


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