title: Bach1-mediated suppression of p53 is inhibited by p19(ARF)  independently of MDM2.
abstract: Cellular senescence prevents the aberrant proliferation of damaged cells. The transcription factor Bach1 binds to p53 to repress cellular senescence, but it is still unclear how the Bach1-p53 interaction is regulated. We found that the Bach1-p53 interaction was inhibited by oncogenic Ras, bleomycin, and hydrogen peroxide. Proteomics analysis of Bach1 complex revealed its interaction with p19(ARF), a tumor suppressor that competitively inhibited the Bach1-p53 interaction when overexpressed within cells. Reduction of MDM2 expression in wild-type murine embryonic fibroblasts (MEFs) did not result in slower proliferation, showing that Bach1 plays a role in keeping the proliferation of MEFs independent of MDM2. Consistent with this interpretation, expression of p21 was highly induced in MEFs when both Bach1 and MDM2 were abrogated. The level of Bach1 protein was reduced on knockdown of p53. These results suggest that p53 activation involves its dissociation from Bach1, achieved in part by the competitive binding of p19(ARF) to Bach1. The p19(ARF)-Bach1 interaction constitutes a regulatory pathway of p53 in parallel with the p19(ARF)-MDM2 pathway.
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hironari
authors.initials: H
authors.lastname: Nishizawa
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ota
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Dohi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism / Q000502:physiology*; D001667:Binding, Competitive; D016922:Cellular Senescence; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2