Chao‐Kai Chou1, Dung‐Fang Lee2,3, Hailin Sun3, Long‐Yuan Li4,5, Chun‐Yi Lin6, Wei‐Chien Huang4,5,3, Jung-Mao Hsu2,3, Hsu-Ping Kuo2,3, Hirohito Yamaguchi3, Ying‐Nai Wang3, Mo Liu2,3, Hsin-Yi Wu7, Pao‐Chi Liao7, Chia-Jui Yen3, Mien‐Chie Hung3
1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
2Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas
3Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
4Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan
5Department of Biotechnology, Asia University, Taichung, Taiwan
6Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University & Hospital, Taichung, Taiwan
7Department of Environment and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Tóm tắt
AbstractMAX dimerization protein 1 (MAD1) is a transcription suppressor that antagonizes MYC‐mediated transcription activation, and the inhibition mechanism occurs mainly through the competition of target genes' promoter MYC binding sites by MAD1. The promoter binding proteins switch between MYC and MAD1 affects cell proliferation and differentiation. However, little is known about MAD1's regulation process in cancer cells. Here, we present evidence that AKT inhibits MAD1‐mediated transcription repression by physical interaction with and phosphorylation of MAD1. Phosphorylation reduces the binding affinity between MAD1 and its target genes' promoter and thereby abolishes its transcription suppression function. Mutation of the phosphorylation site from serine to alanine rescues the DNA‐binding ability in the presence of activated AKT. In addition, AKT inhibits MAD1‐mediated target genes (hTERT and ODC) transcription repression and promotes cell cycle and cell growth. However, mutated S145A MAD1 abrogates the inhibition by AKT. Thus, our results suggest that phosphorylation of MAD1 by AKT inhibits MAD1‐mediated transcription suppression and subsequently activates the transcription of MAD1 target genes. © 2009 Wiley‐Liss, Inc.
