Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer.
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-3beta (GSK-3beta), a key component of the Wnt 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-3beta (p-GSK-3beta) at Ser(9) (an inactivated form of GSK-3beta) 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-3beta 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-3beta. Our results indicate that Mcl-1 stabilization by GSK-3beta inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer.
Ding
Qingqing
Q
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, Usa.
He
Xianghuo
X
Xia
Weiya
W
Hsu
Jung-Mao
JM
Chen
Chun-Te
CT
Li
Long-Yuan
LY
Lee
Dung-Fang
DF
Yang
Jer-Yen
JY
Xie
Xiaoming
X
Liu
Jaw-Ching
JC
Hung
Mien-Chie
MC
D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014466:Ultraviolet Rays
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D019311:Staurosporine