Journal
CANCER RESEARCH
Volume 67, Issue 10, Pages 4564-4571Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-1788
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Funding
- NCI NIH HHS [CA109311, CA 16672, CA099031] Funding Source: Medline
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Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic Bcl-2 family member, is overexpressed in many types of human cancer and associates with cell immortalization, malignant transformation, and chemoresistance. Glycogen synthase kinase-3 (GSK-3 beta), a key component of the Writ signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3 (p-GSK-3 beta) at Ser9 (an inactivated form of GSK-3 beta) in multiple cancer cell lines and primary human cancer samples. In addition, Mcl-1 was strikingly linked with poor prognosis of human breast cancer, in which the high level of Mcl-1 was related to high tumor grade and poor survival of breast cancer patients. Furthermore, we found that activation of GSK-30 could down-regulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3 beta. Our results indicate that Mcl-1 stabilization by GSK-3 beta inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer.
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