Author(s): Yin L, Kharbanda S, Kufe D
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Abstract Resistance of carcinoma cells to hypoxic stress is of importance to the growth of solid tumors. The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by most human carcinomas; however, there is no known relationship between MUC1 and the hypoxic stress response. The present work has demonstrated that MUC1 attenuates activation of hypoxia-inducible factor-1alpha (HIF-1alpha), a regulator of gene transcription in the response of cells to hypoxic stress. In cells with stable gain and loss of MUC1 function, we have shown that MUC1 up-regulates prolyl hydroxylase 3 (PHD3) expression and promotes HIF-1alpha degradation. PHD activity is attenuated by increases in reactive oxygen species (ROS) generated in the hypoxic stress response. Our results further demonstrate that MUC1 blocks hypoxia-induced increases in ROS and thereby potentiates PHD-mediated HIF-1alpha suppression. Importantly, MUC1 also blocks hypoxia-induced apoptosis and necrosis by suppressing accumulation of ROS. These findings indicate that MUC1 attenuates HIF-1alpha activation in a survival response to hypoxic stress.
This article was published in J Biol Chem
and referenced in Journal of Glycobiology