title: The suppression of MAD1 by AKT-mediated phosphorylation activates MAD1 target genes transcription.
abstract: MAX 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Lin
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ying-Nai
authors.initials: YN
authors.lastname: Wang
authors.forename: Mo
authors.initials: M
authors.lastname: Liu
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Wu
authors.forename: Pao-Chi
authors.initials: PC
authors.lastname: Liao
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D016259:Genes, myc; D006801:Humans; D013058:Mass Spectrometry; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt