Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis.
Mol Cancer Res 2004 Sep
PMID:Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types. 1538 27

Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.
Mol Cancer Ther 2004 Nov
PMID:The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells. 1554 78

We compared native Adenoviral (Ad) vectors to a basic Fibroblast Growth Factor-retargeted Adenovirus (FGF2-Ad) for gene delivery into a diverse panel of lung cancer cells in vitro and xenografts in vivo. Cells were first evaluated for vector-specific receptor expression. Marked variations of surface coxsackie-adenovirus receptor (CAR), but relatively similar levels of alpha v integrin and FGF receptor expression were evident. Transduction efficiency by Ad directly correlated (R = 0.77, 95% CI 0.28-0.94, P = 0.0085) with CAR, but not with alpha v integrin expression. Transduction efficiency by FGF2-Ad did not correlate with the measured FGF receptor expression. Blocking studies indicated that gene transfer by FGF2-Ad occurred by a CAR-independent pathway, and could be inhibited by free FGF in a dose-dependent manner. Ad-antiserum inhibited FGF2-Ad gene transfer, suggesting that the Ad-component was needed for post-entry DNA-delivery. Soluble heparin sulfate proteoglycans (HSPG) or alpha v integrin blockers marginally decreased FGF2-Ad transduction. Both Ad and FGF2-Ad equally transduced CAR-positive non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells. By contrast, FGF2-Ad had a distinct transduction advantage in CAR-deficient NSCLC cells. This improvement in transduction of CAR-deficient cells by FGF2-Ad persisted in vivo. These data justify the need for an improved FGF2-Ad vector for clinical use in CAR-deficient lung cancer.
Am J Respir Cell Mol Biol 2005 Mar
PMID:Gene transfer mediated by native versus fibroblast growth factor-retargeted adenoviral vectors into lung cancer cells. 1562 75

CYP1A1, CYP2E1, GSTM1 and GSTT1 polymorphisms were evaluated in north Indian lung cancer patients and controls. The estimated relative risk for lung cancer associated with the CYP1A1*2C allele was 2.68. Apart from the CYP1A1*2C genotype, there was no attributable risk in relation to other genotypes when analyzed singly. However, in the presence of a single copy of the variant CYP1A1 (CYP1A1*1/2A) and null GSTT1 genes, there was a three-fold increased risk for lung cancer; when stratified histologically the relative risk increased to 3.7 in case of SQCC. Similarly individuals carrying the mutant CYP1A1*2C genotype and single copy of the variant CYP1A1 Mspl allele, had a relative risk of 2.85 for lung cancer. In case of the GSTM1 and CYP1A1 genotypes, null GSTM1 and variant Msp1 alleles had two-fold elevated risk for SQCC. On the other hand CYP1A1*2C and null GSTM1 genotype had a 3.5-fold elevated risk for SCLC. Stratified analysis indicated a multiplicative interaction between tobacco smoking and variant CYP1A1 genotypes on the risk for SQCC and SCLC. The heavy smokers (BI > 400) with CYP1A1*2C genotype were at a very high risk to develop SCLC with an OR of 29.30 (95% CI = 2.42-355, p = 0.008). Taken together, these findings, the first to be analyzed in north Indian population, suggest that combined GSTT1 , GSTM1 and CYP1A1 polymorphisms could be susceptible to lung cancer induced by bidi (an Indian cigarette) smoking.
Mol Cell Biochem 2004 Nov
PMID:Genetic polymorphism of the CYP1A1, CYP2E1, GSTM1 and GSTT1 genes and lung cancer susceptibility in a north indian population. 1564 21

N-Oct-3 is a neuronal transcription factor widely expressed in the developing mammalian central nervous system, and necessary to maintain neural cell differentiation. The key role of N-Oct-3 in the transcriptional regulation of a multiplicity of genes is primarily due to the structural plasticity of its so-called 'POU' (acronym of Pit, Oct, Unc) DNA-binding domain. We have recently reported about the unusual dual neuro-specific transcriptional regulation displayed by N-Oct-3 [Blaud,M., Vossen,C., Joseph,G., Alazard,R., Erard,M. and Nieto,L. (2004) J. Mol. Biol., 339, 1049-1058]. To elucidate the underlying molecular mechanisms, we have now made use of molecular modeling, DNA footprinting and electrophoretic mobility shift assay techniques. This combined approach has allowed us to uncover a novel mode of homodimerization adopted by the N-Oct-3 POU domain bound to the neuronal aromatic amino acids de-carboxylase and corticotropin-releasing hormone gene promoters and to demonstrate that this pattern is induced by a structural motif that we have termed 'NORE' (N-Oct-3 responsive element), comprising the 14 bp sequence element TNNRTAAATAATRN. In addition, we have been able to explain how the same structural motif can also induce the formation of a heterodimer in association with hepatocyte nuclear factor 3beta(/Forkhead box a2). Finally, we discuss the possible role of the NORE motif in relation to neuroendocrine lung tumor formation, and in particular the development of small cell lung cancer.
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PMID:Identification of the 'NORE' (N-Oct-3 responsive element), a novel structural motif and composite element. 1576 76

Interleukin-6 (IL-6) has been identified as an important growth regulator of lung cancer cells. Elevation of serum levels of IL-6 has been found in a subpopulation of lung cancer patients, but rarely in patients with benign lung diseases. Approximately 15% of non-small cell lung cancer (NSCLC) tumors exhibit neuroendocrine (NE) properties (NSCLC-NE) and have been suggested to have the biological characteristics similar to small cell lung cancer (SCLC) with early metastasis and initial responsiveness to chemotherapy. We recently showed that IL-6 promotes cell proliferation and downregulates the expression of neuron-specific enolase (NSE, one of the major NE markers) in NSCLC-NE cells. In this study, we show that IL-6 stimulates a transient increase of tyrosine phosphorylation of STAT3 in a dose-dependent fashion. Inhibition of STAT3 signaling pathway by either AG-490 (JAK2-specific inhibitor) or overexpression of STAT3Y705F (a dominant-negative STAT3) reverses NSE expression in IL-6- treated NSCLC-NE cells. In addition, IL-6 induces phosphorylation and activation of p38 MAPK. SB-203580, a p38 MAPK-specific inhibitor, inhibits IL-6-induced p38 MAPK phosphorylating activity and suppresses IL-6-stimulated cell proliferation. Together, our results indicate that STAT3 signaling pathway is involved in IL-6-induced NE differentiation and that p38 MAPK is associated with IL-6-stimulated growth regulation in NSCLC-NE cells. These data suggest that both kinase pathways play critical roles in the pathogenesis of NSCLC-NE malignancies, providing new molecular targets for future therapeutic approaches.
Am J Physiol Lung Cell Mol Physiol 2005 Sep
PMID:IL-6 induces neuroendocrine dedifferentiation and cell proliferation in non-small cell lung cancer cells. 1589 58

DNA topoisomerase I (Topo I) is a molecular target for the anticancer agent topotecan in the treatment of small cell lung cancer and ovarian carcinomas. However, the molecular mechanisms by which topotecan treatment inhibits cancer cell proliferation are unclear. We describe here the identification of Topo I as a novel endogenous interaction partner for transcription factor c-Jun. Reciprocal coimmunoprecipitation analysis showed that Topo I and c-Jun interact in transformed human cells in a manner that is dependent on JNK activity. c-Jun target gene epidermal growth factor receptor (EGFR) was identified as a novel gene whose expression was specifically inhibited by topotecan. Moreover, Topo I overexpression supported c-Jun-mediated reporter gene activation and both genetic and chemical inhibition of c-Jun converted cells resistant to topotecan-elicited EGFR downregulation. Topotecan-elicited suppression of proliferation was rescued by exogenously expressed EGFR. Furthermore, we demonstrate the cooperation of the JNK-c-Jun pathway, Topo I, and EGFR in the positive regulation of HT-1080 cell proliferation. Together, these results have identified transcriptional coactivator Topo I as a first endogenous cofactor for c-Jun in the regulation of cell proliferation. In addition, the results of the present study strongly suggest that inhibition of EGFR expression is a novel mechanism by which topotecan inhibits cell proliferation in cancer therapy.
Mol Cell Biol 2005 Jun
PMID:DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation. 1592 21

Small cell lung cancer (SCLC) patients suffer from pulmonary stresses such as dyspnea and chest pain, and the pathogenic mechanisms are not known. SCLC cells secrete a variety of bioactive neuropeptides, including bombesin-like peptides. We hypothesize that these peptides may enhance the sensitivity of the pulmonary chemosensitive nerve endings, contributing to the development of these pulmonary stresses in SCLC patients. This study was therefore carried out to determine the effects of bombesin and gastrin-releasing peptide (GRP), a major bombesin-like peptide, on the sensitivities of pulmonary chemoreflex and isolated pulmonary vagal chemosensitive neurons. In anesthetized, spontaneously breathing rats, intravenous infusion of bombesin or GRP significantly amplified the pulmonary chemoreflex responses to chemical stimulants such as capsaicin and ATP. The enhanced responses were completely abolished by perineural capsaicin treatment of both cervical vagi, suggesting the involvement of pulmonary C-fiber afferents. In isolated pulmonary vagal chemosensitive neurons, pretreatment with bombesin or GRP potentiated the capsaicin-induced Ca(2+) transient. This sensitizing effect was further demonstrated in patch-clamp recording studies; the sensitivities of these neurons to both chemical (capsaicin and ATP) and electrical stimuli were significantly enhanced by the presence of either bombesin or GRP. In summary, our results have demonstrated that bombesin and GRP upregulate the pulmonary chemoreflex sensitivity in vivo and the excitability of isolated pulmonary chemosensitive neurons in vitro.
Am J Physiol Lung Cell Mol Physiol 2005 Dec
PMID:Sensitization of pulmonary chemosensitive neurons by bombesin-like peptides in rats. 1604 Jun 30

A single monoclonal antibody (MAG-1) directed against the C-terminal 18-amino acid region (VAGc18) of provasopressin was examined as an agent for recognizing the tumor-specific NRSA marker common to small cell lung cancer (SCLC) in formalin-fixed tissues with ABC immunohistochemistry. SCLC tumors were obtained from several tissue locations and included primary, metastatic, and recurrent disease. Positive staining was found in 91% of cases (53/58). All five of the unreactive tumors were of the lungs or chest wall, and there did not appear to be an association of this negativity with disease stage, age, or sex. Alternatively, almost all primary lesions, almost all metastatic lesions, and all recurrent lesions examined gave a positive reaction with MAG-1. For this study, vasopressin-producing cells of the human anterior hypothalamus served as a positive control, while negative controls comprised normal lung tissue, tumor that received MAG-1 in the presence of an excess of antigen (VAGc18 peptide), or tumor reacted with a commercial IgG1 isotype as primary antibody. All of the results indicate that MAG-1 can be effectively used to selectively identify the NRSA marker on almost all SCLC tumors, at all disease stages, and at all locations. Since all four tumors tested showing no reactivity with MAG-1 gave a positive reaction for synaptophysin, it is proposed that a combined use of MAG-1 with synaptophysin antibodies could allow all SCLC tumors to be detected by ABC immunohistochemistry.
Appl Immunohistochem Mol Morphol 2005 Dec
PMID:Immunohistochemical detection of NRSA on small cell lung cancer with a monoclonal antibody (MAG-1) that recognizes the carboxyl terminus of provasopressin. 1628 Jun 67

Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic cancer.
Cell Mol Life Sci 2006 Mar
PMID:Hedgehog signaling in pancreas development and disease. 1646 49


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