Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Transl Psychiatry ; 2: e119, 2012 May 22.
Article in English | MEDLINE | ID: mdl-22832964

ABSTRACT

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.


Subject(s)
Black or African American/genetics , Smoking/genetics , Adult , Aged , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 15/genetics , Female , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Nerve Tissue Proteins/genetics , Phenotype , Polymorphism, Single Nucleotide/genetics , Proteoglycans/genetics , Receptors, Nicotinic/genetics , Statistics as Topic
2.
Br J Cancer ; 83(12): 1688-95, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11104567

ABSTRACT

Data from basic research suggests that amplification of the proto-oncogene c-myc is important in breast cancer pathogenesis, but its frequency of amplification and prognostic relevance in human studies have been inconsistent. In an effort to clarify the clinical significance of c-myc amplification in breast cancer, we conducted a comprehensive literature search and a meta-analysis in which 29 studies were evaluated. The weighted average frequency of c-myc amplification in breast tumours was 15.7% (95% CI = 12.5-18.8%), although estimates in individual studies exhibited significant heterogeneity, P<0.0001. C-myc amplification exhibited significant but weak associations with tumour grade (RR = 1.61), lymph-node metastasis (RR = 1.24), negative progesterone receptor status (RR = 1.27), and postmenopausal status (RR = 0.82). Amplification was significantly associated with risk of relapse and death, with pooled estimates RR = 2.05 (95% CI = 1.51-2.78) and RR = 1.74 (95% CI = 1.27-2.39), respectively. This effect did not appear to be merely a surrogate for other prognostic factors. These results suggest that c-myc amplification is relatively common in breast cancer and may provide independent prognostic information. More rigorous studies with consistent methodology are required to validate this association, and to investigate its potential as a molecular predictor of specific therapy response.


Subject(s)
Breast Neoplasms/genetics , Gene Amplification , Genes, myc/genetics , Breast Neoplasms/pathology , Female , Humans , Predictive Value of Tests , Prognosis , Proto-Oncogene Mas
3.
Oncogene ; 19(10): 1307-17, 2000 Mar 02.
Article in English | MEDLINE | ID: mdl-10713672

ABSTRACT

Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFalpha enhanced the process. In c-myc transgenic mice, c-myc expression was high in the hyperplastic mammary epithelium and in the majority of tumor areas. However, the tumors displayed focal areas of low expression of c-myc but high rates of proliferation. In contrast to E2F1 and cyclin A2, which were induced and co-localized with c-myc expression, induction of cyclins D1 and E occurred only in these tumor foci. Overexpression of cyclin D1 also occurred in the hyperplastic epithelium of tgfalpha-single and tgfalpha/c-myc-double transgenic mice. In tgfalpha/c-myc tumors, cells positive for cyclins D1 and E were randomly spread, without showing a reciprocal relationship to c-myc expression. In contrast to c-myc tumors, most tgfalpha/c-myc tumors showed undetectable levels of retinoblastoma protein (pRB), and the loss of pRB occurred in some cases at the mRNA level. These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGFalpha may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.


Subject(s)
Carrier Proteins , Cell Cycle Proteins , Cell Transformation, Neoplastic/genetics , DNA-Binding Proteins , Mammary Neoplasms, Experimental/genetics , Proto-Oncogene Proteins c-myc/genetics , Transforming Growth Factor alpha/genetics , Animals , Apoptosis , Cell Cycle/genetics , Cyclin A/isolation & purification , Cyclin D1/isolation & purification , Cyclin D3 , Cyclin E/isolation & purification , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclins/isolation & purification , E2F Transcription Factors , E2F1 Transcription Factor , Epithelial Cells , Female , In Situ Hybridization , In Situ Nick-End Labeling , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Transgenic , Models, Biological , Retinoblastoma Protein/isolation & purification , Retinoblastoma-Binding Protein 1 , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor DP1 , Transcription Factors/isolation & purification
4.
J Cell Sci ; 109 ( Pt 6): 1615-22, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8799848

ABSTRACT

CS-1 melanoma cells transfected with cDNAs encoding either the beta 3 or beta 5 integrin subunit protein express alpha v beta 3 or alpha v beta 5, respectively, enabling them to adhere to vitronectin yet only alpha v beta 3 promotes cell spreading and migration on this substrate. Following exposure to insulin or insulin-like growth factor, alpha v beta 5-expressing CS-1 cells gain the ability to migrate on vitronectin. To identify structural regions in beta 3 or beta 5 that account for these distinct biological properties, CS-1 cells were transfected with one of two chimeric beta subunit proteins, in which the ecto- and cytoplasmic domains of beta 3 and beta 5 were exchanged (termed alpha v beta 3/5 or alpha v beta 5/3). Surprisingly, alpha v beta 3/5 expressing cells spread and migrate on vitronectin while cells expressing alpha v beta 5/3 do not unless they are exposed to cytokine. These findings suggest that the distinct migratory properties mediated by integrins alpha v beta 3 and alpha v beta 5 and their response to cytokine activation is determined by a sequence(s) within the ectodomain of the integrin beta subunit.


Subject(s)
Antigens, CD/physiology , Cell Movement/physiology , Integrin beta Chains , Integrins/physiology , Platelet Membrane Glycoproteins/physiology , Animals , Antigens, CD/chemistry , Antigens, CD/genetics , Cell Adhesion/physiology , Cricetinae , Humans , Integrin beta3 , Integrins/chemistry , Integrins/genetics , Molecular Structure , Platelet Membrane Glycoproteins/chemistry , Platelet Membrane Glycoproteins/genetics , Protein Conformation , Receptors, Vitronectin/chemistry , Receptors, Vitronectin/genetics , Receptors, Vitronectin/physiology , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/physiology , Transfection , Tumor Cells, Cultured , Vitronectin/metabolism
5.
J Cell Biol ; 130(2): 441-50, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7542248

ABSTRACT

The NPXY sequence is highly conserved among integrin beta subunit cytoplasmic tails, suggesting that it plays a fundamental role in regulating integrin-mediated function. Evidence is provided that the NPXY structural motif within the beta 3 subunit, comprising residues 744-747, is essential for cell morphological and migratory responses mediated by integrin alpha v beta 3 in vitro and in vivo. Transfection of CS-1 melanoma cells with a cDNA encoding the wild-type integrin beta 3 subunit, results in de novo alpha v beta 3 expression and cell attachment, spreading, and migration on vitronectin. CS-1 cells expressing alpha v beta 3 with mutations that disrupt the NPXY sequence interact with soluble vitronectin or an RGD peptide, yet fail to attach, spread, or migrate on immobilized ligand. The biological consequences of these observations are underscored by the finding that CS-1 cells expressing wild-type alpha v beta 3 acquire the capacity to form spontaneous pulmonary metastases in the chick embryo when grown on the chorioallantoic membrane. However, migration-deficient CS-1 cells expressing alpha v beta 3 with mutations in the NPXY sequence lose this ability to metastasize. These findings demonstrate that the NPXY motif within the integrin beta 3 cytoplasmic tail is essential for alpha v beta 3-dependent post-ligand binding events involved in cell migration and the metastatic phenotype of melanoma cells.


Subject(s)
Cell Movement , Integrins/physiology , Melanoma, Experimental/pathology , Neoplasm Metastasis , Receptors, Cytoadhesin/physiology , Amino Acid Sequence , Animals , Base Sequence , Cell Adhesion , Chick Embryo , Cricetinae , Glycoproteins/metabolism , Integrins/chemistry , Integrins/genetics , Lung Neoplasms/secondary , Melanoma, Experimental/secondary , Molecular Sequence Data , Mutation , Oligopeptides/metabolism , Phenotype , Receptors, Cytoadhesin/chemistry , Receptors, Cytoadhesin/genetics , Receptors, Vitronectin , Tumor Cells, Cultured , Vitronectin
SELECTION OF CITATIONS
SEARCH DETAIL
...