Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclins and cyclin-dependent kinases (cdk) have been identified as important regulators of cell replication. Molecular alteration in the cdk pathways appear to be important in cancer with some cyclins (eg cyclin D and E) proposed to be oncogenes and some inhibitors of cdk (eg p16) proposed to be tumor suppressor genes. In human breast carcinoma cell line MDA361 both cyclin D and E are overexpressed and cdk 4 and 6 are the predominate kinases which phosphorylate retinoblastoma protein and to a greater extent a novel 88 kDa protein. This 88 kDa protein was detected as a significant substrate in five of seven breast carcinoma cell lines, three lung carcinoma cell lines as well as in primary breast and lung epithelium. Normal human and murine T lymphocytes and established lymphoid cell lines are devoid of this protein and minimal amounts were detected in normal human fibroblast. In contrast to retinoblastoma protein, the 88 kDa protein appears to be more prevalent in the cytosolic than the nuclear subfraction. The phosphorylation of this 88 kDa protein by the G1 associated cdks suggest that this protein may represent another targeted substrate regulating the G1 phase of the cell cycle.
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PMID:A novel cytoplasmic substrate for cdk4 and cdk6 in normal and malignant epithelial derived cells. 747 27

The bombesin-like peptides can function as autocrine growth factors in lung cancer and candidate tumor suppressor genes on chromosomes 3 and 9 play important roles in lung cancer. Bombesin-like peptides can function as mitogens for normal bronchial epithelial cells and lung cancer cell lines. The monoclonal antibody directed against gastrin releasing peptide and bombesin, 2A11, can inhibit the growth of small cell lung cancer in vitro and in vivo and intravenous administration has induced a clinical remission in a patient with relapsed small cell lung cancer. The loss of a portion of one of the two short arms of chromosome 3 (3p) is identified in nearly 100% of tumor cell lines and tumors from patients with small cell lung cancer. Introduction of chromosome 3 into tumor cell lines suppresses their tumorigenicity in athymic nude mice, one of the characteristics of the cancer phenotype. Both copies of the candidate tumor suppressor gene on chromosome 9, CDKN2, are deleted in approximately one-fourth of lung cancer cell lines examined and the protein product of CDKN2, p16 is undetectable in one-third of the lung cancer cell lines studied. The CDKN2 gene is inactivated more commonly in non-small cell lung cancer than small cell lung cancer while the retinoblastoma gene is inactivated more commonly in small cell lung cancer than non-small cell lung cancer. It appears that a single defect in this cell cycle pathway is necessary for unregulated growth in lung cancer and current evidence suggests these defects differ between small cell and non-small cell lung cancer.
Lung Cancer 1995 Jun
PMID:Biology of small cell lung cancer. 755 56

Chromosome band 9p21 is deleted frequently in non-small cell lung carcinoma (NSCLC), and the p15 and p16 cyclin-dependent kinase-4 inhibitor genes map within this deletion region. Recent studies demonstrated deletion of p15 and p16 in NSCLC metastases and cell lines, suggesting a role for these genes in NSCLC progression. We now report p15 and p16 copy number, as determined by fluorescence in situ hybridization with a P1 contig, in 18 primary NSCLCs. Codeletion of p15 and p16 was found in 15 of 18 NSCLCs, and 1 of the 3 tumors with normal p15 and p16 copy number had a nonsense mutation in exon 2 of p16. We conclude that p15 and p16 are deleted and/or mutated in most primary NSCLCs. Two observations, however, support the involvement of at least one additional tumor suppressor gene on chromosome 9. These observations are: (a) the large size (> 100 kb) of most NSCLC p15/p16 deletions; and (b) the absence of exon 2 mutations in most retained NSCLC p15 and p16 alleles.
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PMID:Codeletion of p15 and p16 genes in primary non-small cell lung carcinoma. 760 11

To elucidate the possibility of the existence of multiple tumor suppressor genes on chromosome arm 9p, we performed genetic and epigenetic analyses of the CDKN2A/p16/MTS1 and CDKN2B/p15/MTS2 genes as well as homozygous deletion mapping of 9p in human lung carcinoma. To avoid overlooking genetic alterations due to contamination of noncancerous cells, we examined 32 non-small cell lung carcinoma (NSCLC) and 16 cell small cell lung carcinoma (SCLC) cell lines. (CDKN2A was mutated or homozygously deleted in 20 (63%) of 32 NSCLC cell lines, and methylation of the CpG island in the CDKN2A gene was detected in six of the 12 cell lines carrying the wild-type CDKN2A gene. Although homozygous deletions of the CDKN2B gene were also detected in NSCLC cell lines with CDKN2A deletions, mutation and methylation in the CDKN2B gene were infrequent. Thus, it was indicated that the CDKN2A gene rather than the CDKN2B gene plays a critical role as a tumor suppressor gene in NSCLC. Homozygous deletions on 9p were detected in 14 (44%) NSCLC cell lines. It is of note that two common regions of homozygous deletions were mapped proximal to the CDKN2A and CDKN2B loci, suggesting that tumor suppressor genes other than CDKN2A are present on 9p. In contrast to NSCLC, homozygous deletions on 9p as well as CDKN2A and CDKN2B alterations were infrequent in SCLC. Therefore, the pathogenetic significance of 9p alterations is likely to differ between SCLC and NSCLC.
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PMID:Association of CDKN2A(p16)/CDKN2B(p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma. 962 35

p16, an inhibitor of cell cycle machinery, is frequently inactivated in non-small cell carcinoma of the lung (NSCCL). To clarify the significance of p16 inactivation in the progression of lung adenocarcinoma, we immunohistochemically evaluated p16 protein status and Rb, p53 and cyclin D1 expression in 51 surgically resected adenocarcinomas that were less than 3 cm in diameter (median follow-up period: 52.5 months). Twenty-one of 51 adenocarcinomas showed negative immunostaining for p16. Twenty adenocarcinomas were also negative for Rb, while 31 and 13 were positive for p53 and cyclin D1, respectively. Loss of p16 expression was significantly correlated with scar grade, lymphatic permeation, lymph node metastasis and clinical stage. Rb protein expression was also inversely correlated with scar grade, pleural involvement and vascular invasion. When the cases were stratified according to the expression of both proteins, the Rb-/p16- subset (7/51) consisted of poorly differentiated adenocarcinoma with a higher grade of invasion. While Rb, p53 and cyclin D1 protein status showed no significant correlations with prognosis, p16 inactivation was significantly correlated with poor prognosis, and the prognosis of Rb-/p16- was the worst among the 4 subsets. Inactivation of p16 may play a role in accelerating scar formation and lymph node metastasis, and may contribute through these mechanisms to poor prognosis in patients with small-sized lung adenocarcinoma.
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PMID:p16 inactivation in small-sized lung adenocarcinoma: its association with poor prognosis. 998 32

The geranylgeranyltransferase I inhibitor GGTI-298 has recently been shown to arrest human tumor cells in the G1 phase of the cell cycle, induce apoptosis, and inhibit tumor growth in nude mice. In the present manuscript, we provide a possible mechanism by which GGTI-298 mediates its tumor growth arrest. Treatment of the human lung carcinoma cell line Calu-1 with GGTI-298 results in inhibition of the phosphorylation of retinoblastoma protein, a critical step for G1/S transition. The kinase activities of two G1/S cyclin-dependent kinases, CDK2 and CDK4, are inhibited in Calu-1 cells treated with GGTI-298. Furthermore, GGTI-298 has little effect on the expression levels of CDK2, CDK4, CDK6, cyclins D1 and E, but decreases the levels of cyclin A. GGTI-298 increases the levels of the cyclin-dependent kinase inhibitors p21 and p15 and had little effect on those of p27 and p16. Most interesting is the ability of GGTI-298 to induce partner switching for several CDK inhibitors. GGTI-298 promotes binding of p21 and p27 to CDK2 while decreasing their binding to CDK6. Reversal of partner switching and G1 block was observed after removal of GGTI-298. Furthermore, GGTI-298 treatment results in an increased binding of p15 to CDK4, which is paralleled with decreased binding to p27. The results demonstrate that the GGTI-298-mediated G1 block in Calu-1 cells involves increased expression and partner switching of CDK inhibitors resulting in inhibition of CDK2 and CDK4, and retinoblastoma protein phosphorylation.
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PMID:The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. 1006 46

Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Many genes that regulate the critical cell cycle checkpoint at G1S are altered in human tumors. These genetic changes can result in uncontrolled cellular proliferation, genetic instability, and altered response to radiation and chemotherapy. The p53 tumor suppressor gene serves a critical role at the G1S transition, where it can either block entry into S phase or activate programmed cell death (apoptosis) in response to DNA damage. p53 Gene mutations are common in human tumors and interfere with the activation of apoptosis in response to most chemotherapeutic agents. Paclitaxel is a potent chemotherapeutic agent that interferes with mitotic spindle function to block cells at G2M, the most radiosensitive phase of the cell cycle. Utilization of paclitaxel as a radiation sensitizer in vivo to treat aggressive, locally advanced neoplasms has resulted in high response rates and acceptable toxicity in protocols for non-small cell lung carcinoma, upper gastrointestinal tract carcinoma, and other malignancies. Recent evidence suggests that paclitaxel is unique in its ability to activate apoptosis in tumor cells with p53 mutations in vitro and in vivo. The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma. The effects of p16(INK4a) alterations in response to paclitaxel/radiation and the risk of systemic relapse are currently being evaluated. Information about molecular genetic alterations in individual tumors ultimately may be a critical factor in choosing between therapeutic options.
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PMID:Role of p53 and p16 gene alterations in determining response to concurrent paclitaxel and radiation in solid tumor. 1021 May 35

The p16INK4A tumor suppressor gene is frequently inactivated in non-small cell lung carcinoma (NSCLC) and is less frequently inactivated in small cell lung carcinoma (SCLC) by mutation, deletion or DNA methylation. There are several reports that the reintroduction of the p16INK4A gene into p16(-) NSCLC cells results in significant growth suppression. However, there have been no reports of reintroduction of the p16INK4A gene into SCLC cells. To assess the biological significance of p16INK4A inactivation in the development of SCLC, full-length p16INK4A cDNA was introduced into an SCLC cell line, Ms-13, in which the p16INK4A protein was not detected. SCLC cells stably transfected with the p16INK4A expression vector formed only 2-16% of the number of neomycin-resistant colonies formed by cells transfected with a control vector, and no expression of exogenous p16INK4A protein was detected in any of 16 expanded clones. Transient transfection of the p16INK4A gene into SCLC cells resulted in exogeneous p16INK4A protein expression and dephosphorylation of endogenous retinoblastoma (RB) protein. These results suggest that the restoration of the p16INK4A function suppresses the growth of SCLC cells by dephosphorylation of the RB protein. Therefore, inactivation of p16INK4A may play an important role in the enhancement of growth of p16INK4A(-) RB(+) SCLC tumors in vivo.
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PMID:Activation of RB tumor suppressor protein and growth suppression of small cell lung carcinoma cells by reintroduction of p16INK4A gene. 1033 60

Inactivation of the Rb pathway in non-small cell lung carcinoma (NSCLC) occurs mostly through inactivation of the cyclin-dependent kinase inhibitor p16(INK4A) and/or up-regulation of cyclin D1. In order to assess the frequency and the prognostic value of these abnormalities in NSCLC, immunohistochemical analysis of Rb, p16(INK4), and cyclin D1 has been performed on 168 cases of NSCLC including 77 squamous cell carcinomas, 43 adenocarcinomas, and 48 basaloid carcinomas. The reduced survival rate of basaloid carcinoma (stage I-II) compared with other histological types of NSCLC was confirmed (p = 0.008). Loss of protein expression of Rb and p16(INK4A) was observed in 12 per cent and 58 per cent of NSCLC cases respectively and cyclin D1 overexpression in 43 per cent. There was an inverse correlation between Rb and p16 expression ( p < 0.0001) and a direct correlation between Rb and cyclin D1 expression ( p = 0.0007). In univariate analysis, Rb-negative adenocarcinomas at stages I-II had a significantly shorter survival than Rb-positive cases ( p = 0.04) and stages I-II p16-positive cases had a shorter survival than p16-negative cases ( p = 0.02), which was more significant in basaloid carcinoma ( p = 0.003). p16 status retained its influence on survival in multivariate analysis at stage I-II for all cases ( p = 0.01) and for basaloid carcinoma ( p = 0.005). Cyclin D1 overexpression did not influence survival. Combined Rb/p16/cyclin D1 phenotypes in univariate analysis showed a shorter survival for Rb-negative/p16-positive/cyclin D1-negative tumours ( p = 0.002). These results, linked to previous data, indicate that the Rb pathway of G1 arrest is initially disrupted in the vast majority of NSCLCs (83 per cent), but could not confirm an unfavourable role for each individual event (p16(INK4A) loss or cyclin D1 up-regulation) in prognosis.
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PMID:Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. 1044 Jul 42

The p16 protein is encoded by the CDKN2 gene, and functions as an inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6). Phosphorylation of the retinoblastoma protein (pRb) by CDK4/6 represents a vital step in cell cycle progression. Alterations of p16INK4A are frequent events in human malignancies. In non-small cell lung carcinoma (NSCLC) the data concerning the mechanisms of p16INK4A inactivation suggest that point mutations and aberrant methylation of its promoter can only account for a proportion of the cases with abnormal p16 immunoexpression. The role of deletions in this procedure is not yet clarified. In order to gain more insight into the role of deletions in p16INK4A deregulated expression, we investigated the state of the chromosomal region 9p21-22 in a series of 57 NSCLCs, by performing a detailed mapping analysis, using a tight cluster of highly polymorphic microsatellite markers, and correlating the findings with p16 immunostaining. Abnormal p16 expression was observed in 46% of the NSCLCs examined. No relationship was observed between p16 abnormal staining and various clinicopathological parameters. Abnormal p16 protein staining was strongly associated with hemizygous deletions at the IFNA and D9S171 microsatellite loci, which demarcate the region encoding the p16INK4A gene (P = 0.002). These findings suggest that deregulated expression of p16 is involved in the multistage process of NSCL carcinogenesis and that deletions may represent a predominant mechanism of p16INK4A inactivation. A significant percentage also of LOH was noticed at the D9S162 (35%) and D9S126 (38%) loci which lie 6cM and 4cM, respectively, far from the area which encodes p16INK4A, implying that other tumor suppressor genes (TSGs) may reside in this region. Although the overall incidence of LOH at the examined region was high (58%), we did not observe any correlation with smoking habits, histology and lymph node status. Another noteworthy finding was the existence of microsatellite instability (MI) in 11% of the patients. MI provides a marker for replication error phenotype (RER+), a recently defined manifestation of genetic instability observed in a wide range of tumors. In conclusion, alterations (LOH + MI) at the 9p21-22 chromosome region are frequent events in NSCLCs and may affect directly or indirectly the expression of p16.
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PMID:Aberrant p16 expression is correlated with hemizygous deletions at the 9p21-22 chromosome region in non-small cell lung carcinomas. 1047 Jan 33


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