p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y.
Histone deacetylase (HDAC) inhibitors cause growth arrest at the G1 and/or G2/M phases, and induce differentiation and/or apoptosis in a wide variety of tumour cells. The growth arrest at G1 phase by HDAC inhibitors is thought to be highly dependent on the upregulation of p21/WAF1, but the precise mechanism by which HDAC inhibitors cause G2/M arrest or apoptosis in tumour cells is unknown. Gadd45 causes cell cycle arrest at the G2/M phase transition and participates in genotoxic stress-induced apoptosis. We show here that it is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter, in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and electrophoretic mobility shift assays. These revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that the transcription factors Oct-1 and NF-Y specifically bind to each site. Thus, HDAC inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.
Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan.
Tohru
T
Hirose
Yoshihiro
Y
Sowa
Senye
S
Takahashi
Shoichi
S
Saito
Chikako
C
Yasuda
Nobuaki
N
Shindo
Kiyoshi
K
Furuichi
Toshiyuki
T
Sakai
D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D051863:Host Cell Factor C1; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D050811:Octamer Transcription Factor-1; D012516:Osteosarcoma / Q000473:pathology; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000097642:GADD45 Proteins
D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D051863:Host Cell Factor C1; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D050811:Octamer Transcription Factor-1; D011506:Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C497692:HCFC1 protein, human; C494165:POU2F1 protein, human; C012589:trichostatin A