Mucin 1 oncoprotein blocks hypoxia-inducible factor 1alpha activation in a survival response to hypoxia.
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.
Yin
Li
L
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kharbanda
Surender
S
Kufe
Donald
D
D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018396:Mucin-1 / Q000737:chemistry*; D009336:Necrosis; D015513:Oncogene Proteins / Q000737:chemistry*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species; D015854:Up-Regulation
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018396:Mucin-1; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D011393:Procollagen-Proline Dioxygenase