RESUMEN
Aberrant Wnt/beta-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli (APC) is thought to initiate colon adenoma formation. Using zebrafish and human cells, we show that homozygous loss of APC causes failed intestinal cell differentiation but that this occurs in the absence of nuclear beta-catenin and increased intestinal cell proliferation. Therefore, loss of APC is insufficient for causing beta-catenin nuclear localization. APC mutation-induced intestinal differentiation defects instead depend on the transcriptional corepressor C-terminal binding protein-1 (CtBP1), whereas proliferation defects and nuclear accumulation of beta-catenin require the additional activation of KRAS. These findings suggest that, following APC loss, CtBP1 contributes to adenoma initiation as a first step, whereas KRAS activation and beta-catenin nuclear localization promote adenoma progression to carcinomas as a second step. Consistent with this model, human FAP adenomas showed robust upregulation of CtBP1 in the absence of detectable nuclear beta-catenin, whereas nuclear beta-catenin was detected in carcinomas.
Asunto(s)
Adenoma/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Oxidorreductasas de Alcohol/metabolismo , Neoplasias del Colon/metabolismo , Proteínas de Unión al ADN/metabolismo , Adenoma/genética , Adenoma/patología , Poliposis Adenomatosa del Colon/patología , Animales , Diferenciación Celular , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Transducción de Señal , Pez Cebra , beta Catenina/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Proteínas ras/metabolismoRESUMEN
Attrition in intervention programs for domestically violent men is considered to be a serious and enduring problem. Researchers have found a number of sociodemographic variables that partially explain this phenomenon; however, models based on these variables have a limited predictive power. Scott (2004) argues that a firm theoretical base is needed in future investigations of the problem and suggests the use of the transtheoretical model of behavior change (TTM), which was found to predict dropout with accuracy in other areas of behavioral change. This study investigated the relationship between four TTM constructs (Stages of Change, Decisional Balance, Self-Efficacy, and Processes of Change) and premature termination with a sample of Canadian French-speaking men (N = 302) in five domestic violence treatment programs. Contrary to the initial hypotheses, the TTM constructs did not predict dropout. Discussion investigates how social desirability bias affects results being obtained by current TTM measures and whether more motivation to change at intake necessarily relates to involvement in treatment for longer periods of time.