Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We investigated whether intraalveolar inflammatory cells such as alveolar macrophages or lymphocytes produced the gene product of a type-C human endogenous retrovirus (HERV), HERV-E 4-1, which might initiate an immune response resulting in interstitial lung disease. We evaluated HERV-E 4-1 Env protein production by bronchoalveolar lavage fluid (BALF) cells and PBL in 109 patients with sarcoidosis, idiopathic pulmonary fibrosis (IPF), lung cancer, and rheumatoid lung disease as well as 26 normal control individuals. Production of HERV-E 4-1 Env protein by alveolar macrophages was observed using indirect immunofluorescence in 3 IPF patients and 3 sarcoidosis patients (6/135). No peripheral blood lymphocytes showed HERV-E 4-1 Env protein production. Antibodies to HERV-E 4-1 Env protein were detected in the BALF of all six patients by immunoblot analysis, while none of the normal control individuals showed HERV-E 4-1 Env protein antibody in the BALF. All examined BALF cells showed HERV-E 4-1 env mRNA transcript expression by reverse transcription-polymerase chain reaction. No significant influence of point mutation or DNA polymorphism on HERV-E 4-1 Env protein production was recognized. In conclusion, local production of HERV-E 4-1 Env protein and defective tolerance of HERV gene products with resultant antibody production may contribute to the pathogenesis of IPF or sarcoidosis in some patients.
Am J Respir Cell Mol Biol 1997 Apr
PMID:Alveolar macrophages produce the Env protein of a human endogenous retrovirus, HERV-E 4-1, in a subgroup of interstitial lung diseases. 911 54

An inhibitory effect on both constitutive and inducible expression of cytochrome P450 isoenzymes has been shown for different cytokines and growth factors. We previously described an inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 mRNA and enzyme activity by transforming growth factor-beta1 (TGF-beta1) in human lung cancer A549 cells. In the present study, we report that not only TCDD-induced expression of CYP1A1 but also basal mRNA expression of CYP1A1, CYP1B1, and aryl hydrocarbon receptor (AHR) was down-regulated by TGF-beta1 in cells not treated with TCDD. In contrast, mRNA expression of the AHR partner protein Arnt (aryl hydrocarbon receptor nuclear translocator) was not influenced. Furthermore, TCDD-induced expression of CYP1B1 and NMO-1 was inhibited, and the IC50 values of 5-10 pM TGF-beta1 were in the same range as observed for inhibition of CYP1A1 and AHR mRNA expression. Transfection studies with a plasmid containing a luciferase reporter gene under control of two dioxin-responsive elements indicate an effect on AHR protein expression. Results of time-course studies revealed a parallel inhibition of AHR and CYP1 mRNA expression, indicating that TGF-beta1 is a direct negative regulator of transcription of these genes. The treatment of cells with cycloheximide led to a superinduction of TCDD-induced CYP1A1 and CYP1B1 mRNA expression and abolished the inhibitory effect of TGF-beta1 on basal as well as TCDD-induced CYP1 and AHR mRNA expression. TGF-beta1 seems not to influence the stability of AHR mRNA. The results suggest that TGF-beta1 induces rapid transcription and translation of an as-yet-unknown negative regulatory factor or factors that may directly regulate expression of AHR and genes of Ah gene battery.
Mol Pharmacol 1997 May
PMID:Effect of transforming growth factor-beta1 on expression of aryl hydrocarbon receptor and genes of Ah gene battery: clues for independent down-regulation in A549 cells. 914 8

Cytokeratins form part of the cytoskeleton of both normal and malignant epithelium. A novel tumor marker measuring cytokeratin 19 (CK-19) fragment has been introduced and proven to be suitable for monitoring therapy and following cases of non-small cell lung cancer, squamous cell lung cancer in particular. However, whether the serum level of CK-19 fragment reflects the number of proliferating tumor mass remains unknown. We studied the CK-19 fragment produced by two human squamous cell lung cancer cell lines. In Western blotting analysis, culture supernatants of both cell lines displayed bands of 37 and 40 kDa, which represented the CK-19 fragment and the intact CK-19, respectively. Gel filtration demonstrated that a part of soluble CK-19 was released as a large complex form in culture supernatants. The level of CK-19 fragment in culture supernatants increased during the exponential growth phase. CK-19 level decreased by an addition of a cytotoxic agent to non-significant level though the transient release of CK-19 fragment occurred during the first 2 days. After all, soluble CK-19 fragments were detected in culture supernatants of human lung cancer cell lines and its level reflected proliferating cancer cells though it was not determined whether CK-19 fragments were released directly from live cells.
Am J Respir Cell Mol Biol 1997 May
PMID:Production of cytokeratin 19 fragment by human squamous lung cancer cell lines. 916 Aug 42

The antiestrogen tamoxifen is thought to antagonize the effects of estrogens by competing with them for estrogen receptor (ER) binding. However, tarnoxifen can also reverse multidrug resistance, synergize with cisplatin cytotoxicity, and inhibit growth in ER-negative lung cancer cells. In addition to ERs, rat and human target tissues contain a second binding macromolecule termed the type II estrogen binding site (type II EBS). It has been shown that tamoxifen and flavonoids, a widely distributed class of natural substances with a variety of biologic actions, bind to type II EBS and inhibit the growth of several tumor cell types. At present, conflicting data about ERs and an absence of data about type II EBSs exist for lung tumors. We have tested non-small-cell lung carcinoma cell lines and primary tumor cells for the presence of ERs and type II EBSs and have evaluated the effects of tamoxifen and quercetin (pentahydroxyflavone) on the growth of these cells. Using a whole-cell assay and nuclear and cytosolic radiobinding experiments with [3H]estradiol as tracer, we have found that SK-LU1, SW900, ChaGo-K-1, H441, H661, and A549 cells, as well as primary tumors, bind estrogen specifically. This binding results mainly from the presence of a large number of type II EBSs, whereas ERs are absent or present at low concentrations. Type II EBSs bound tamoxifen and quercetin with similar affinity. Cell counts and a thymidine incorporation assay showed that both compounds inhibit cell growth in a concentration-dependent manner at concentrations ranging from 10 nM to 1 microM. Neither ipriflavone, an isoflavone, nor rutin, the 3-rhamnosylglucoside of quercetin, bound type II EBSs or inhibited cell growth. These findings suggest that tamoxifen and quercetin could regulate lung cancer cell growth through a binding interaction with type II EBSs. This mechanism could also be active in vivo, in that we have observed that nuclear and cytosolic type II EBSs were present in all primary lung cancers tested (n = 12), and that tamoxifen and quercetin were effective in inhibiting in vitro bromodeoxyuridine (BrdU) incorporation and proliferation-cell nuclear antigen expression by neoplastic cells in these cancers.
Am J Respir Cell Mol Biol 1997 Jul
PMID:Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer. 922 9

To investigate mechanisms causing p53 mutations in lung cancer cases, relations between p53 gene mutations and aetiological factors such as smoking history or family history of cancers cases. The contribution of genotypes related to carcinogen metabolism (CYP1A1 and GSTM1) was also analysed. p53 mutations were observed in 13 cases (37.5%). Seven (53.8%) of the 13 patients with p53 mutation compared with five (22.7%) of 22 patients without had a family history of cancer. However, there was no significant relation between p53 mutation or family history of cancer and CYP1A1 or GSTM1 genotypes. In conclusion, p53 mutation might be associated with the inherited characteristics that result in familial aggregation of lung cancer; however, this association was not explained by genotypes of enzymes related to carcinogen metabolisms.
Mol Pathol 1997 Apr
PMID:p53 gene mutations, and CYP1A1 and GSTM1 genotypes in pulmonary squamous cell carcinomas. 923 Nov 61

The mitochondrial DNA (mtDNA) of hair follicles was used for studying the genotoxicity of smoking-mediated carcinogens. We determined the incidences of the 4,977 bp and 7,436 bp mtDNA deletions, tandem duplication in the D-loop region and the proportion of the 4,977 bp deleted mtDNA (dmtDNA) in the total DNA of hair follicles from 213 male non-smokers and 74 male smokers, respectively. Twenty-three patients with lung cancer were also investigated. We found that the current cigarette smokers had a 3.1 times higher average incidence of the 4,977 bp dmtDNA (RR: 3.1, P < 0.001) as compared with non-smokers, and this mtDNA deletion was especially prevalent in the old heavy smokers. For the smokers of the age above 70, the average incidence of the 4,977 bp dmtDNA was 3.7 times higher in the group with a smoking index of 401-800 (RR: 3.7, P < 0.005) and 3.2 times higher in the group with a smoking index greater than 800 (RR: 3.2, P < 0.005). However, there was no statistically significant relationship between the incidence of the 7,436 bp dmtDNA and the smoking index, although there was a mild increase in the percentage of the 7,436 bp dmtDNA with the increase of the consumption of cigarettes. No tandem duplication of mtDNA in the D-loop region was disclosed in either smokers or non-smokers group. The proportions of the 4,977 bp dmtDNA in hair follicles were found to correlate with age, but did not keep increasing with cigarette consumption except in the group of subjects with a smoking index of less than 400. On the other hand, we found that the average proportion of the 4,977 bp dmtDNA in the hair follicles was 1.201 +/- 0.371% for the patients with lung cancer who had a smoking index greater than 400, while that was only 0.146% for the age-matched healthy smokers with the same smoking index. In conclusion, the high incidence of the 4,977 bp dmtDNA of hair follicles is not only associated with aging but also correlated with the amount of cigarette smoking. A high proportion of the 4,977 bp dmtDNA in the hair follicles may be considered one of the molecular events that are associated with the occurrence of smoking-associated cancers.
Environ Mol Mutagen 1997
PMID:Smoking-associated mitochondrial DNA mutations in human hair follicles. 925 29

Immunoglobulin production stimulating activity of alcohol dehydrogenase [EC 1.1.1.1] was assessed. Alcohol dehydrogenase-I (ADH-I) derived from horse liver stimulated IgM production by human-human hybridoma, HB4C5 cells producing human lung cancer specific monoclonal IgM. IgM production of HB4C5 cells was enhanced more than 6 fold by the addition of ADH-I at 400 microg/ml under serum-free condition. However, yeast derived ADHs, such as ADH-II and -III were ineffective to accelerate immunoglobulin production of the hybridoma line. These results imply that the immunoglobulin production stimulating effect of ADH-I is irrelevant to its enzymatic function, and defined as a novel feature of ADH-I. This enzyme also stimulated IgM and IgG production by human peripheral blood lymphocytes 2.9 fold and 1.4 fold, respectively. This fact suggests that ADH-I stimulates immunoglobulin production not only by specific hybridoma cell line, but also by non-specific immunoglobulin producers.
Mol Cell Biochem 1997 Aug
PMID:Alcohol dehydrogenase-I from horse liver stimulates immunoglobulin production by human hybridoma and human peripheral blood lymphocytes. 927 61

To better understand the mechanism(s) underlying lung cancer invasion and metastasis, a Transwell invasion chamber was used to select progressively more invasive cancer cell populations from a clonal cell line of human lung adenocarcinoma, CL1. Five sublines with progressive invasiveness, designated CL1-1, CL1-2, CL1-3, CL1-4, and CL1-5, were obtained through this in vitro selection process. Their invasive abilities through basement membrane matrix showed a 4- to 6-fold increase over that of the parental cells. Moreover, the sublines manifested an increase in their colony-forming ability on soft agar, tumorigenicity, and metastatic potency in severe combined immunodeficiency (SCID) mice. Examining the phenotypes of the cell lines revealed increased expression of 92 kD gelatinase and an increase in the cell population stained with anti-keratin-8 and -18 antibodies. Clonal isolation of anti-keratin-18-antibody-positive and -negative cell populations demonstrated a correlated enhancement of the invasiveness of these cells and their expression of keratin-18. These results support the notion that the metastatic behavior of lung cancer cells can be characterized with this in vitro system, and that the properties of these progressively invasive cancer cells can be clonally studied.
Am J Respir Cell Mol Biol 1997 Sep
PMID:Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. 930 22

Significant interindividual variations in health outcome may be caused by the inheritance of variant polymorphic genes, such as CYP2D6 and CYP2E1 for activation, and GSTM1 and GSTT1 for detoxification of chemicals. However, mechanistic studies linking the inheritance of predisposing genes with genotoxic effects towards cancer have yet to be systematically conducted. We have studied 54 lung cancer patients and 50 matched normal controls, who have been cigarette smokers, to elucidate the role of polymorphic genes in cancer. Our data indicates that the inheritance of unfavorable CYP2D6, CYP2E1, and GSTT1 genes in strongly correlated with the smoking-related lung cancer. For heavy cigarette smokers (> 30 pack-years), the smoking habit is the strongest predictor of lung cancer risk irrespective of the inheritance of unfavorable metabolizing genes. For moderate to light smokers (< 30 pack-years), the genetic predisposition plays an important role for the risk (odds ratio = 3.46; 95% Cl = 0.46-40.2). Using a subgroup of the study population, we observed that cigarette smokers having the defective GST genes have significantly more chromosome aberrations as determined by the fluorescence-in-situ-hybridization (FISH) technique than smokers with the normal GST genes (P < 0.001). In conclusion, our study provides data to indicate that individuals who have inherited unfavorable metabolizing genes have increased body burden of toxicants to cause increased genetic damage and to have increased risk for cancer. Studies like ours can be used to understand the basis for interindividual variations in cancer outcome, to identify high risk individuals and to assess health risk.
Environ Mol Mutagen 1997
PMID:Interactions between genetic predisposition and environmental toxicants for development of lung cancer. 932 44

The purpose of the present communication was to determine in lung cancer patients and healthy donors if there was a possible association between cancer and biomarkers of cytogenetic damage and ras p21 oncoprotein levels, and if various exogenous confounding factors (such as smoking habit) and endogenous ones (age, sex, etc.) could affect these biomarkers. Peripheral blood and plasma were collected from 31 lung cancer patients prior to treatment and 35 healthy donors of a similar socioeconomic status and from the same region in Poland. Chromosomal aberrations (CA), sister chromatid exchanges (SCE), high frequency cells (HFC), and proliferative rate index (PRI) were examined from the blood and ras p21 oncoproteins from the plasma. These parameters were used as biomarkers of genotoxic anomalies. All the biomarkers were examined for their relationship to confounding factors of age, sex, smoking habit, and immediate family cancer history. Results were analyzed by a t-test, analysis of variance (ANOVA), and stepwise multivariate regression analysis. All types of CA (including and excluding gaps), percent aberrant cells, SCE, and ras p21 oncoproteins were statistically significantly higher in cancer patients than in the healthy donors. Although there were smaller numbers of females in the cancer patients group who were older than the males, there was a difference due to sex (gender) with statistically significant increases in females for CA, SCE, and HFC, but there was no increase for ras p21 oncoproteins. Cytogenetic damage was not related to other cancers in the immediate families of the groups. All major CA parameters differed significantly between smokers and non-smokers in the cancer patients group, and SCE and HFC differed in the healthy donors group. Such parameters also showed a significant variability with the number of cigarettes smoked and the years of smoking habit. Multivariate regression analyses showed a significant association between cytogenetic damage, ras p21 oncoproteins, and cancer. In conclusion, cytogenetic damage and ras p21 oncoproteins in this study appear to be biomarkers associated with cancer, but have not been proved causally, and confounding factors such as age, sex (gender), and smoking can have an impact on them.
Environ Mol Mutagen 1997
PMID:Factors affecting various biomarkers in untreated lung cancer patients and healthy donors. 932 45


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