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

The p16IN4/CDKN2/MTS1 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16INK4a, which regulates retinoblastoma protein-dependent G1 arrest, and a cell cycle inhibitor designated p19ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16INK4a has been described as a frequent event in lung cancer, the current function of p19ARF is still poorly understood. We have examined the expression of the human p19ARF (hp19ARF) protein in a large series of lung cancers using immunohistochemistry and showed that the protein was more frequently lost in high-grade neuroendocrine (NE) lung tumors (large cell NE carcinoma and small cell lung carcinoma; 51 of 78, 65%) than it was in non-small cell lung cancer (25 of 101, 25%). No deleterious mutation was found in exons 1beta and 2 of hp19ARF in those NE tumors with negative immunoreactivity, and a beta transcript was detected in the majority of them. Concomitant absence of hp19ARF and retinoblastoma proteins was frequently detected in high-grade NE lung tumors, whereas no relationship could be found between the status of hp19ARF and p53 proteins in those tumors. These results are consistent with an alternative growth suppressor function for hp19ARF in NE lung cancer that is distinct from that of p16INK4a. Moreover, the frequent uncoupling between the beta transcript and the hp19ARF protein suggests a novel mechanism of inactivation at the translational level.
 ...
PMID:The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. 973 4

Uncontrolled proliferation is the characteristic of cancer. Several kinds of genes control the cell cycle: oncogenes, tumor suppressor genes, and genes implicated in apoptosis or survival. Two major pathways of control are frequently disrupted in human cancer. The first one is the RB pathway with inactivation of the RB protein (retinoblastoma protein), either by alteration of the retinoblastoma gene itself, or by genetic alterations of the genes implicated in RB phosphorylation. The second one is the inactivation of the p53 protein. Both of these abnormalities are described in human lung carcinoma but differ according to histologic subtype.
 ...
PMID:[Cell cycle, tumor suppressor genes and lung cancers]. 980 56

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.
 ...
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

The retinoblastoma gene family is composed of three members: the retinoblastoma gene, one of the most studied tumor suppressor genes, and two related genes: p107 and pRb2/p130. These proteins are also known as the pocket proteins due to a unique structural and functional domain composed of subdomains A and B separated by a spacer region that is highly conserved among each of the proteins. These proteins exhibit unique growth suppressive properties that are cell type specific, suggesting that although the pocket proteins may complement each other, they are not fully functionally redundant. With the development of antibodies recognizing these three proteins it is now possible to detect expression in formalin-embedded specimens. Recent studies on 235 lung cancers, using immunohistochemical techniques, suggested an independent role for Rb2/p130 in the development and/or progression of human lung carcinoma. We found a statistically significant inverse relationship between the histological grading (degree of malignant potential) and the expression of pRb/p105, p107 and pRb2/p130 in squamous cell carcinomas, meaning that an increase in grading resulted in a significant decrease in protein expression. This phenomenon was particularly evident for pRb2/p130 (p < .0001) which had the highest percentage of undetectable levels in all the specimens examined and the tightest inverse correlation (p value) with both the histological grading and PCNA expression in the most aggressive tumor types, suggesting an important role for pRb2/p130 in the pathogenesis and progression of certain lung cancers. We further explored the expression of pRb2/p130 protein in routine archival FNAB cytological material from 30 Patients with lung cancer using immunocytochemical techniques, comparing protein expression with tumor type. Two pathologists evaluated the staining pattern and scored the percentage of positive cells. Of the 30 neoplasms, 27 displayed a positive staining for pRb2/p130. In particular, we detected pRb2/p130 in 9 (100%) squamous carcinomas, 11 (84%) adenocarcinomas, 5 (100%) BAC, and 2 (66%) SCC. The percentage of positive nuclei varied in different tumors with the highest expression level in adenocarcinomas. Immunocytochemistry represents a sensitive method for detection of pRb2/p130 expression in cytological or archival specimens, and the level of detection seems to be comparable to paraffin sections. Therefore, this methodology could be used in the preoperative evaluation of routine cytological specimens in order to improve the diagnostic and prognostic evaluation of lung cancer patients.
 ...
PMID:The role of pRb2/p130 protein in diagnosing lung carcinoma on fine needle aspiration biopsies. 1009 23

Fourteen cases (13 pleural and one intrapulmonary) of solitary fibrous tumors (SFTs) (the so-called fibrous mesothelioma) were studied. The lesions occurred more in females (nine cases) than males (five cases). The age of patients ranged from 44 to 73 years old (median 60 years). The tumors presented as cough with or without blood-tinged sputum, exertional dyspnea, chest pain, nausea, body weight loss, fever, or as asymptomatic masses detected by routine chest radiograph. Two patients with huge (tumor larger than 20 cm) malignant tumors had accompanying pleural effusion and one associated with hypoglycemia. Ten benign tumors measured 2-11 cm (median size 7 cm) while the remaining four histologically malignant ones measured 20-30 cm in size. All of them were well circumscribed and thinly encapsulated. Hemorrhage and necrosis were more frequently seen in the malignant tumors. Histologically, these lesions were characterized by 'patternless pattern' with occasional hemangiopericytic features (three cases). The tumor cells were all immunoreactive for vimentin, CD 34, and focally actin-positive in one case, but not for keratin, desmin, S-100 protein, carcinoembryonic antigen, alpha 1-ACT and F VIII-related antigen, supported a primitive mesenchymal origin. p53 protein was expressed in two of the malignant cases. Proliferating cell nuclear antigen stain was positive with 50 and 80% of the labeling index in the benign and malignant tumors, respectively, but retinoblastoma gene protein was negative in all tumors. This analysis confirmed the relationship between histological malignant SFTs and tumor size, cellularity, mitotic activity, necrosis and tumor suppressor gene expression. However, the clinical behavior was unpredictable. Complete respectability seemed to be the most important indicator of clinical outcome in the less aggressive tumors.
Lung Cancer 1999 Jan
PMID:Thoracic solitary fibrous tumor: clinical and pathological diversity. 1010 Jan 46

Small cell carcinoma is a rare neoplasm in the esophagus. To evaluate cell proliferation activity and its underlying mechanisms in this tumor, we examined immunohistochemically 5 cases of small cell carcinoma of the esophagus (SCCE) for expressions of tumor suppressor proteins, oncoproteins and cell proliferation markers including p53, p21WAF1/CIP1, retinoblastoma (Rb) protein, bcl-2, Ki-67 and PCNA, and compared the results with those of 5 cases of small cell carcinoma of the lung (SCCL) and 10 cases of squamous cell carcinoma of the esophagus (SQCE). The prevalence and labeling index of p53-immunoreactivity tended to be higher in SCCE (4/5; 56.6%) and SCCL (4/5; 79.9%) than in SQCE (6/10; 48.8%). Expression of p21WAF1/CIP1 was observed in 2 of 10 cases of SQCE. In contrast, its expression could not be detected in any cases of SCCE and SCCL examined. Expression of Rb protein was observed in 9 out of 10 cases of SQCE, but not in any cases of SCCE and SCCL. SCCE and SCCL showed more frequent and intense immunoreactivity for bcl-2 than SQCE. In expression of cell proliferation markers (Ki-67 and PCNA), no remarkable difference was observed among SCCE, SCCL and SQCE. These results suggest that SCCE and SCCL could share some genetic alternations including mutation of p53, loss of Rb gene and overexpression of bcl-2, and these may be related to the similar biological potentials between the two. Furthermore, SCCE was different from SQCE in expression of Rb protein and bcl-2, and these two types of esophageal carcinoma could arise through different molecular mechanisms.
 ...
PMID:Immunohistochemical analysis for cell proliferation-related protein expression in small cell carcinoma of the esophagus; a comparative study with small cell carcinoma of the lung and squamous cell carcinoma of the esophagus. 1021 9

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.
 ...
PMID:Activation of RB tumor suppressor protein and growth suppression of small cell lung carcinoma cells by reintroduction of p16INK4A gene. 1033 60

Increased protein expression of the G1 cyclins D1 and E is reported in invasive non-small cell lung carcinoma. However, during transformation of the bronchial epithelium, overexpression of these species occurs, and their relationship to aberrant expression of p53 and retinoblastoma (Rb) has not been described previously. To determine the expression of these cell cycle regulators during the development of invasive squamous cell carcinoma (SCC) of the lung, the immunohistochemical expression patterns in normal bronchial epithelium (n = 36), squamous metaplasia (SM; n = 28), and epithelial atypia (n = 34) were compared with that in low-grade dysplasia (LGD; n = 17), high-grade bronchial dysplasia (HGD; n = 30), and SCC (n = 36). Monoclonal anti-p53 Pab1801, polyclonal anti-cyclin D1 DCS6, monoclonal anti-cyclin E HE12, and monoclonal anti-Rb OP-66 antibodies were used. Cyclin D1 was not expressed in normal bronchial epithelium but was detected in 7% of SMs, 15% of atypias; 18% of LGDs, 47% of HGDs, and 42% of SCCs. Cyclin E was not detected in normal epithelium (n = 24), SM (n = 16), or LGD (n = 12), but it was found in 9% of atypias (2 of 22), 33% of HGDs (7 of 21), and 54% of SCCs (13 of 24). p53 was not expressed in normal epithelium, SM, and LGD, but it was overexpressed in 6% of atypias, 53% of HGDs, and 61% of SCCs. Abnormal Rb expression was found only in 2 of 36 cases of SCC. A total of 91% of HGDs and 92% of SCCs exhibited overexpression of at least one of the p53, cyclin D1, or cyclin E species. However, no link was observed between overexpression of p53 and the overexpressed G1 cyclins in preneoplastic lesions. Overexpression of cyclin D1, cyclin E, and p53 occurs frequently and independently in pulmonary SCC and is detected in lesions before the development of invasive carcinoma. In contrast, altered Rb expression is a late and infrequent event in squamous cell carcinogenesis.
 ...
PMID:Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. 1034 60

We have previously identified an inverse relationship between p53 and retinoblastoma protein (pRb) immunoreactivity in non-small cell carcinoma of the cervix. Because pRb is infrequently expressed in small cell carcinoma of the lung, we analyzed 25 small cell neuroendocrine carcinomas of the cervix to test the hypotheses that 1) lack of pRb expression is associated with the neuroendocrine phenotype in human papillomavirus (HPV)-associated cervical carcinoma and 2) the inverse relationship between p53 and pRb immunoreactivity also occurs in these tumors. HPV type was analyzed by PCR, HPV distribution by in situ hybridization and expression of p53 and pRb by immunohistochemistry. All of the tumors contained HPV sequences, with 13 tumors HPV 16 positive, 11 HPV 18 positive, and 1 HPV 45 positive. In situ hybridization showed large intranuclear dot-like signals in all positive tumors, suggesting viral integration. No multiple infections were identified. Expression of retinoblastoma protein was not detectable in 23 tumors (92%), the remaining two showing only weak, focal expression. Expression of p53 protein was variable in distribution and intensity. It did not correlate with HPV type, and there was no relationship with pRb immunoreactivity. These data indicate that, although there is no reciprocal relationship between p53 and pRb immunoreactivity in these tumors, retinoblastoma protein is infrequently expressed in HPV-containing small cell neuroendocrine carcinoma of the cervix, irrespective of infecting HPV type. This is consistent with the reported findings in small cell carcinoma of the lung and suggests that the small cell neuroendocrine phenotype may be related to the abrogation of retinoblastoma protein function.
 ...
PMID:Loss of retinoblastoma protein expression is frequent in small cell neuroendocrine carcinoma of the cervix and is unrelated to HPV type. 1045 2

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.
 ...
PMID:Aberrant p16 expression is correlated with hemizygous deletions at the 9p21-22 chromosome region in non-small cell lung carcinomas. 1047 Jan 33


<< Previous 1 2 3 4 5 6 7 8 9 Next >>