Assuntos
Doença Celíaca , Erros de Diagnóstico/prevenção & controle , Dieta Livre de Glúten/métodos , Comportamento Alimentar/fisiologia , Glutens/metabolismo , Antígenos HLA-DQ , Adulto , Idade de Início , Doenças Assintomáticas/epidemiologia , Doença Celíaca/diagnóstico , Doença Celíaca/dietoterapia , Doença Celíaca/epidemiologia , Doença Celíaca/etiologia , Doença Celíaca/imunologia , Doença Celíaca/fisiopatologia , Criança , Interação Gene-Ambiente , Antígenos HLA-DQ/análise , Antígenos HLA-DQ/genética , Humanos , Intestino Delgado/imunologia , Intestino Delgado/patologia , Prevalência , Medição de Risco , Fatores de Risco , Testes Sorológicos/métodos , Fatores Sexuais , Avaliação de Sintomas/métodosRESUMO
Past research has inconsistently distinguished the neural substrates of various types of working memory. Task design and individual performance differences are known to alter patterns of brain response during working-memory tasks. These task and individual differences may have produced discrepancies in imaging findings. This study of 50 healthy adults (M(age) = 19.6 yr., SD = .8) examined performance during various parametric manipulations of a verbal and spatial n-back working-memory task. Performance systematically dissociated on the basis of working-memory load, working memory type, and stimulus difficulty, with participants having greater accuracy but slower response time during conditions requiring verbal versus spatial working memory. These findings hold implications for cognitive and neuroimaging studies of verbal and spatial working memory and highlight the importance of considering both task design and individual behavior.
Assuntos
Encéfalo/fisiologia , Memória/fisiologia , Tempo de Reação/fisiologia , Percepção Espacial/fisiologia , Comportamento Verbal/fisiologia , Adolescente , Adulto , Discriminação Psicológica/fisiologia , Feminino , Humanos , Individualidade , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Estimulação Luminosa , Desempenho Psicomotor/fisiologia , Projetos de Pesquisa , Análise e Desempenho de TarefasRESUMO
Stratified squamous epithelial cells undergo an orderly process of cell cycle arrest following detachment from the basement membrane. The basal layer cells which adhere to the basement membrane express telomerase, which maintains the ends of chromosomes in this rapidly dividing population. Non-dividing suprabasal cells downregulate telomerase activity. However, the mechanisms regulating this inhibition are unknown. We examined the regulation of telomerase expression in anchorage-deprived normal human epidermal keratinocytes and squamous cell carcinoma lines. Anchorage-deprived cells underwent rapid loss of telomerase activity. Attachment loss was associated with increased ERK1 activity, G1 to S phase progression, and subsequent G2 arrest. Adhesion to collagen via specific integrin subunits inhibited ERK1 activity and telomerase repression. Loss of telomerase expression was associated with recruitment of an Rb/HDAC1 repressor complex to the -98 E2F site of the hTERT promoter. We propose a mechanism by which anchorage deprivation inhibits telomerase activity in stratified squamous epithelial cells and squamous cell carcinoma lines.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Diferenciação Celular , Células Epiteliais/metabolismo , Telomerase/metabolismo , Sítios de Ligação , Western Blotting , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Carcinoma de Células Escamosas/patologia , Ciclo Celular , Linhagem Celular Tumoral , Células Cultivadas , Colágeno Tipo IV/farmacologia , Ciclina A/análise , Ciclina B/análise , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Flavonoides/farmacologia , Citometria de Fluxo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1 , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase/genéticaRESUMO
BACKGROUND: Integrin-extracellular matrix interactions activate signaling cascades such as mitogen activated protein kinases (MAPK). Integrin binding to extracellular matrix increases tyrosine phosphorylation of focal adhesion kinase (FAK). Inhibition of FAK activity by expression of its carboxyl terminus decreases cell motility, and cells from FAK deficient mice also show reduced migration. Paxillin is a focal adhesion protein which is also phosphorylated on tyrosine. FAK recruitment of paxillin to the cell membrane correlates with Shc phosphorylation and activation of MAPK. Decreased FAK expression inhibits papilloma formation in a mouse skin carcinogenesis model. We previously demonstrated that MAPK activation was required for growth factor induced in vitro migration and invasion by human squamous cell carcinoma (SCC) lines. METHODS: Adapter protein recruitment to integrin subunits was examined by co-immunoprecipitation in SCC cells attached to type IV collagen or plastic. Stable clones overexpressing FAK or paxillin were created using the lipofection technique. Modified Boyden chambers were used for invasion assays. RESULTS: In the present study, we showed that FAK and paxillin but not Shc are recruited to the beta1 integrin cytoplasmic domain following attachment of SCC cells to type IV collagen. Overexpression of either FAK or paxillin stimulated cancer cell migration on type IV collagen and invasion through reconstituted basement membrane which was dependent on MAPK activity. CONCLUSIONS: We concluded that recruitment of focal adhesion kinase and paxillin to beta1 integrin promoted cancer cell migration via the mitogen activated protein kinase pathway.
