MUC1 oncoprotein regulates Bcr-Abl stability and pathogenesis in chronic myelogenous leukemia cells.
ABSTRACT Chronic myelogenous leukemia (CML) results from expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1 heterodimeric protein is aberrantly overexpressed in diverse human carcinomas. The present studies show that MUC1 is expressed in the human K562 and KU812 CML cell lines. The results show that MUC1 associates with Bcr-Abl through a direct interaction between the Bcr N-terminal region and the MUC1 cytoplasmic domain. Stable silencing of MUC1 decreased cytoplasmic Bcr-Abl levels by promoting Bcr-Abl degradation. Silencing MUC1 was also associated with decreases in K562 and KU812 cell self-renewal capacity and with a more differentiated erythroid phenotype. The results further show that silencing MUC1 increases sensitivity of CML cells to imatinib-induced apoptosis. Analysis of primary CML blasts confirmed that, as found with the CML cell lines, MUC1 blocks differentiation and the apoptotic response to imatinib treatment. These findings indicate that MUC1 stabilizes Bcr-Abl and contributes to the pathogenesis of CML cells by promoting self renewal and inhibiting differentiation and apoptosis.
Article: Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress.[show abstract] [hide abstract]
ABSTRACT: The DF3/MUC1 transmembrane oncoprotein is aberrantly overexpressed by most human carcinomas. Certain insights are available regarding a role for MUC1 in intracellular signaling; however, no precise function has been ascribed to this molecule. The present results demonstrate that MUC1 expression is up-regulated by oxidative stress and that this response is mediated by activation of MUC1 gene transcription. A role for MUC1 in the oxidative stress response is supported by the demonstration that MUC1 expression is associated with attenuation of endogenous and H2O2-induced intracellular levels of reactive oxygen species (ROS). MUC1-dependent regulation of ROS is mediated at least in part by up-regulation of anti-oxidant enzyme (superoxide dismutase, catalase, and glutathione peroxidase) expression. In concert with these findings, we show that the apoptotic response to oxidative stress is attenuated by a MUC1-dependent mechanism. These results support a model in which activation of MUC1 by oxidative stress provides a protective function against increased intracellular oxidant levels and ROS-induced apoptosis.Journal of Biological Chemistry 10/2003; 278(37):35458-64. · 4.77 Impact Factor