The suppression of MAD1 by AKT-mediated phosphorylation activates MAD1 target genes transcription

Chao Kai Chou, Dung Fang Lee, Hui Lung Sun, Long Yuan Li, Chun Yi Lin, Wei Chien Huang, Jung Mao Hsu, Hsu Ping Kuo, Hirohito Yamaguchi, Ying Nai Wang, Liu Mo, Hsin Yi Wu, Pao Chi Liao, Chia Jui Yen, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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 DNAbinding 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.

Original languageEnglish
Pages (from-to)1048-1058
Number of pages11
JournalMolecular Carcinogenesis
Volume48
Issue number11
DOIs
Publication statusPublished - 2009 Nov

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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