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)

The retinoblastoma susceptibility gene (Rb) has been characterized as a tumour suppressor gene. Rb protein is involved in cell-cycle control, regulating gene transcription. The absence of Rb protein in inherited retinoblastoma has been proved to be the result of inactivation of both Rb alleles through mutation or deletion, according to the general model for suppressor genes. The frequent detection of Rb gene alterations in human tumours (retinoblastoma, osteosarcoma, bladder carcinoma, small-cell lung carcinoma) and the correlation with clinical outcome found in some tumours prompted us to study Rb gene expression in lymphoid tumours in an attempt to determine whether Rb gene expression is related to histological type and degree of aggressivity in human lymphomas. To establish normal levels of Rb protein, its expression was analysed in vitro on cytospin preparations from normal and pokeweed mitogen (PWM) or phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs), using a monoclonal antibody (PMG3-245). Rb protein expression in vivo was quantified using a computer analysis system (CAS) on frozen sections from reactive and neoplastic lymphoid tissue. As a control of tissue preservation, and to compare Rb expression and growth fraction, the tumours and cells were labelled simultaneously with the Ki67 monoclonal antibody. Normal and stimulated lymphocytes showed a gradual increase of Rb protein during progression of the cell cycle, with a peak in the M phase. G0-G1 cells had no detectable levels of Rb protein, suggesting that the Rb gene may act as a 'status quo' cellular growth fraction control mechanism. In reactive lymphoid tissue, Rb protein was mainly expressed in germinal centres (lymph nodes, tonsils) and cortical thymocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retinoblastoma (Rb) gene product expression in lymphomas. Correlation with Ki67 growth fraction. 850 37

The preclinical studies presented here demonstrate that treatment of human non-small cell lung carcinoma and bladder carcinoma cells by a recombinant adenovirus vector, AdCMVpRB94, expressing the N-terminal truncated retinoblastoma (RB) protein (pRB94) completely suppressed the tumorigenicity of the treated tumor cells in nude mice. Furthermore, gene therapy of established human RB- and RB+ bladder xenograft cancers in nude mice by AdCMVpRB94 resulted in regression of the treated tumors. Of note, although both the full-length and the truncated forms of the RB protein, when overexpressed in tumor cells via replication-deficient adenovirus vectors, were capable of suppression of tumor growth, the pRB94 was evidently more potent than the full-length RB protein.
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PMID:Enhanced tumor suppressor gene therapy via replication-deficient adenovirus vectors expressing an N-terminal truncated retinoblastoma protein. 862 92

The overexpression of N-myc gene and its protein products has been thought to be limited to cases of neuroblastoma, retinoblastoma and small cell lung carcinoma, but there is increasing evidence of its wider distribution in human tumors. This study showed that the protein of N-myc gene is associated in normal, benign and malignant human breast tissues. We found that N-myc oncoprotein is overexpressed in most breast carcinomas and that N-myc overexpression is significantly correlated with clinical stage, and histological grading of the tumors, and, more importantly with the clinical outcome of the patients. Analysis of DNA, mRNA and protein levels suggested that the high N-myc expression in breast cancer occurs without concomitant gene amplification. The finding of a direct inverse correlation between N-myc overexpression and the prognosis of patients with breast carcinoma suggests that N-myc expression may be useful as a prognostic factor in human breast cancer.
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PMID:N-myc protein expression in human breast carcinoma: prognostic implications. 866 86

Work from our laboratory indicates that HLA class II induction by IFN- gamma in the retinoblastoma (RB) protein-defective breast carcinoma line MDA-468-S4 (S4) requires reconstitution of functional RB. To determine whether RB is required for HLA class 11 expression in multiple tumor types, the RB-defective non-small cell lung carcinoma line H2009 and its RB-reconstituted subclones were examined for class II inducibility. Surface HLA-DR (DR) was not inducible by IFN-gamma in H2009. However, unlike the RB-reconstituted subclones of S4, DR surface expression was not detected in the H2009 RB-positive subclones. IFN-gamma induction of CIITA, a major regulator of class II transcription, suggested that H2009 retained at least part of the IFN-gamma signaling pathway leading to class II expression. Examination of class II mRNA indicated that IFN-gamma induction of RB was rescued in the RB-positive subclones of H2009, confirming the requirement for RB for HLA class II inducibility and revealing that RB is required for inducibility in developmentally distinct tumor types. However, DRA inducibility was not rescued in the H2009 RB-positive subclones, which explained the lack of surface DR induction in the RB-positive H2009 subclones. DPA and DPB were also only weakly inducible in the RB-reconstituted H2009 subclones, compared with the previously described, S4 RB-positive subclones. Finally, data reported here indicates that RB's ability to inhibit IFN-gamma-induced apoptosis is not a viable explanation for why RB expression rescues DRB inducibility in H2009.
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PMID:Apoptosis-independent retinoblastoma protein rescue of HLA class II messenger RNA IFN-gamma inducibility in non-small cell lung carcinoma cells. Lack of surface class II expression associated with a specific defect in HLA-DRA induction. 878 10

The retinoblastoma gene family consists of the tumor suppressor protein pRB and its two relatives p107 and p130. These proteins have been implicated in the regulation of cell cycle progression, in part, through inactivation of members of the E2F transcription factor family. Overexpression of pRB, p107, or p130 leads to growth arrest in the G1 phase of the cell cycle, and this arrest is abolished by complex formation with the adenovirus E1A, human papilloma virus E7, or simian virus 40 T oncoproteins. Inactivation of pRB by gross structural alterations or point mutations in the RB-1 gene has been described in a variety of human tumors, including retinoblastomas, osteosarcomas, and small cell lung carcinomas. Despite the structural and functional similarity between pRB, p107, and p130, alterations in the latter two proteins have not been identified in human tumors. We have screened a panel of 17 small cell lung carcinoma cell lines for the presence of functional p107 and p130 by evaluating their ability to form complexes with E1A in vitro. In the GLC2 small cell lung carcinoma cells no p130 protein was detected. The loss of the p130 protein is the result of a single point mutation within a splice acceptor sequence in the GLC2 genomic DNA. This mutation eliminates exon 2, leading to an in-frame stop codon, and no detectable protein is produced. These data are, to our knowledge, the first to describe the loss of p130 as a consequence of a genetic alteration, suggesting that not only pRB but also the other members of the family may contribute to tumorigenesis, providing a rationale for the observation that the DNA tumor viruses selectively target all the members of the retinoblastoma protein family.
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PMID:Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma. 919 69

We have previously reported that HLA class II induction by IFN-gamma is rescuable by reconstitution of functional retinoblastoma protein (RB) in two RB-defective tumour lines: the breast carcinoma line, MDA-468-S4 (S4) and the non-small cell lung carcinoma line, H2009. To determine the range of tumours and tumour types in which RB rescues HLA class II inducibility, we examined another RB-defective tumour line, the retinoblastoma line, WERI-Rb1. As in the case of S4 and H2009, HLA-DRA and -DRB were non-inducible by IFN-gamma in WERI-Rb1. However, neither inducibility of DRA nor DRB mRNA was resulted in an RB-positive stable transformant of WERI-Rb1, WLRB-8. While guanylate-binding protein (GBP) inducibility indicated that the basic IFN-gamma signal transduction pathway remained intact in WERI-Rb1, mRNA for class II transactivator (CIITA), a mediator of the IFN-gamma activation of the HLA class II genes and several other genes related to immune function, was not detectable in IFN-gamma-treated WERI-Rb1, indicating that the lack of CIITA expression was responsible, at least in part, for the inability of RB to rescue HLA class II-inducibility. The HLA class II-associated invariant chain (Ii), the expression of which is also up-regulated by CIITA, was non-inducible in WERI-Rb1, consistent with non-inducible CIITA. Also, IFN-gamma failed to activate the DRA, DRB and Ii promoters in WERI-Rb1. However, exogenous CIITA expression in WERI-Rb1 activated the DRA, DRB and Ii promoter-chloramphinocol acetyltransferase constructs, confirming that CIITA was not induced in WERI-Rb1 and indicating that other proteins required for activation of the class II and Ii promoters were functional in this cell line. Examination of additional cell lines for GBP and CIITA induction revealed that a specific lack of the CIITA IFN-gamma response is common in human tumour lines. The possible role of CIITA defects in tumorigenesis is discussed.
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PMID:IFN-gamma inducibility of class II transactivator is specifically lacking in human tumour lines: relevance to retinoblastoma protein rescue of IFN-gamma inducibility of the HLA class II genes. 931 72

MYCN amplification has been observed in diverse neuronal tumors including neuroblastoma, retinoblastoma, and small cell carcinoma of the lung, and has been correlated with a poor prognosis in advanced-stage neuroblastomas. Recent studies have shown a co-amplification of DDXI, a DEAD box gene, and MYCN in retinoblastoma and neuroblastoma. DDXI has been mapped to within a megabase of the MYCN gene in band 2p24. In the present study, the relational map of DDXI and MYCN by fluorescence in situ hybridization (FISH) mapping to metaphase cells and extended free chromatin fibers indicated that DDXI is telomeric to MYCN. Dual-color FISH analysis of amplicons within arrays of extended chromatin fibers was performed to examine the physical relationship of MYCN and DDXI within double minute chromosomes (dmins) and homogeneously staining regions (hsrs). No regular reiterated amplicon repeat unit was present in the hsrs, but detailed analysis of the configurations of DDXI and MYCN within each array indicated that multiple rearrangements generated a complex hsr amplicon structure. Similarly, analysis of a cell line bearing dmins showed that a composite amplicon structure involving deletions and/or duplications of MYCN and DDXI is a feature of dmin formation. These data are consistent with a molecular mechanism involving many rearrangements during the evolution of gene amplification, resulting in complex amplicon structures with distinct changes in relative gene copy number and considerable variation in intragenic distances between coamplified genes.
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PMID:Relational mapping of MYCN and DDXI in band 2p24 and analysis of amplicon arrays in double minute chromosomes and homogeneously staining regions by use of free chromatin FISH. 936 31

The retinoblastoma (RB) gene plays a key role in cell cycle control by regulation of G1 growth arrest. This gene is inactivated in some human cancers and in most small-cell lung carcinoma (SCLC) cell lines. The aim of this study was to analyze the mechanisms of RB silencing in freshly excised neuroendocrine (NE) tumors embracing the entire spectrum of NE lung neoplasms (typical and atypical carcinoids, large-cell neuroendocrine carcinomas [LCNECs], and SCLCs). To study the role and mechanism of RB inactivation in tumor differentiation and malignant potential, the status of the Rb protein was analyzed in 37 NE lung tumors, using immunohistochemistry with five Rb antibodies. Loss or altered expression of Rb protein was more frequently observed in high-grade NE lung carcinoma (23 of 28, 82%) than in typical and atypical carcinoids (1 of 9, 11%) (P < 0.001). Of 24 tumors with abnormal Rb staining, Southern blotting showed 1 to have undergone rearrangement, SSCP (single-strand conformation polymorphism) and sequencing showed that 6 (25%) exhibited mutations in exons 13-18 or 20-24 of the RB gene, and RT-PCR (reverse transcriptase-polymerase chain reaction) revealed that 14 (58%) showed a low level of or entirely absent RB mRNA (messenger RNA) expression, whereas hypermethylation of the CpG-rich island at the 5' end of the RB gene was not observed. Abnormal Rb protein expression was always associated with one of these three alternative mechanisms in the SCLCs analyzed, but in only 50% of LCNECs. These results indicate that inactivation of the RB gene is highly frequent in freshly excised high-grade NE lung tumors through distinct mechanisms including point mutations and frequent abnormal mRNA expression. Different modes of RB inactivation seem to be implicated along the spectrum of NE lung carcinomas, depending on differentiation state, phenotype, and malignancy grade.
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PMID:Mechanism of retinoblastoma gene inactivation in the spectrum of neuroendocrine lung tumors. 947 5

In this study, we investigated the effect of the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumor type, in a concentration- and time-dependent manner. A dramatic reduction in cell number was observed in adenocarcinoma H460 cells, and was shown to be related to an induction of apoptosis. Bromodeoxyuridine (BrdU) incorporation and flow-cytometric analyses indicated that treatment of H460 cells with AHPN induces cell-cycle arrest at the G1 phase. We therefore investigated the effect of AHPN on several regulatory proteins of the G1 phase of the cell-cycle. The cell-cycle arrest induced by AHPN was accompanied by an inhibition of the hyperphosphorylation of the retinoblastoma (Rb) protein, an indication of G1 arrest. Furthermore, two cyclin-dependent kinases, cdk2 and cdk4, which are normally involved in the phosphorylation of Rb, were shown to have decreased activity. In some cell lines, the decrease in cdk activity may be partly related to an increase in p21(WAF1/Cip1) (p21), an inhibitor of cyclin-dependent kinases. No changes were observed in the cyclin-dependent kinase inhibitor p27(Kip1). The observed increase in p53 in response to AHPN could at least to some extent be responsible for the increased levels of p21. The increase in p53 expression was found to be regulated at a post-transcriptional level. Our results suggest that the growth inhibition of certain lung carcinoma cell lines by AHPN is at least partly related to an increase in p21. However, in other cell lines, different mechanisms appear to be involved. The specificity with which AHPN and other retinoids induce growth arrest and p21 expression indicates that the action of AHPN is not mediated by RAR or RXR receptors, but involves a novel signaling pathway.
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PMID:Inhibition of cell proliferation and induction of apoptosis by the retinoid AHPN in human lung carcinoma cells. 949 Jun 50

Recent studies have demonstrated the importance of E-cadherin, a homophilic cell-cell adhesion molecule, in contact inhibition of growth of normal epithelial cells. Many tumor cells also maintain strong intercellular adhesion, and are growth-inhibited by cell- cell contact, especially when grown in three-dimensional culture. To determine if E-cadherin could mediate contact-dependent growth inhibition of nonadherent EMT/6 mouse mammary carcinoma cells that lack E-cadherin, we transfected these cells with an exogenous E-cadherin expression vector. E-cadherin expression in EMT/6 cells resulted in tighter adhesion of multicellular spheroids and a reduced proliferative fraction in three-dimensional culture. In addition to increased cell-cell adhesion, E-cadherin expression also resulted in dephosphorylation of the retinoblastoma protein, an increase in the level of the cyclin-dependent kinase inhibitor p27(kip1) and a late reduction in cyclin D1 protein. Tightly adherent spheroids also showed increased levels of p27 bound to the cyclin E-cdk2 complex, and a reduction in cyclin E-cdk2 activity. Exposure to E-cadherin-neutralizing antibodies in three-dimensional culture simultaneously prevented adhesion and stimulated proliferation of E-cadherin transfectants as well as a panel of human colon, breast, and lung carcinoma cell lines that express functional E-cadherin. To test the importance of p27 in E-cadherin-dependent growth inhibition, we engineered E-cadherin-positive cells to express inducible p27. By forcing expression of p27 levels similar to those observed in aggregated cells, the stimulatory effect of E-cadherin-neutralizing antibodies on proliferation could be inhibited. This study demonstrates that E-cadherin, classically described as an invasion suppressor, is also a major growth suppressor, and its ability to inhibit proliferation involves upregulation of the cyclin-dependent kinase inhibitor p27.
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PMID:E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). 967 52


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