Oct-1 is involved in the transcriptional repression of the p15(INK4b) gene.
p15(INK4b) functions as a tumor suppressor and implicated in cellular senescence. Here, we show that the Oct-1 binding site in the human p15(INK4b) gene promoter functions as a silencer. Oct-1 specifically interacts with this binding site in vitro and in vivo and SMRT and HDAC1 are present in the p15(INK4b) proximal promoter region. Moreover, mouse embryo fibroblasts (MEFs) lacking Oct-1 have shown significantly increased levels of p15(INK4b) protein compared to their normal counterparts. Treatment with a histone deacetylase (HDAC) inhibitor has activated the expression of p15(INK4b) in wild-type MEFs but has no effect in MEFs lacking Oct-1, suggesting that Oct-1 represses p15(INK4b) gene expression in an HDAC-dependent manner. Finally, we show that the expression of Oct-1 protein significantly decreases, whereas p15(INK4b) protein significantly increases with the cellular aging process. Taken together, these results suggest that Oct-1 is an important transcriptional repressor for p15(INK4b) gene and the transcriptional repression of the p15(INK4b) gene by Oct-1 may be one of the regulatory mechanisms of cellular senescence.
Hitomi
Toshiaki
T
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Matsuzaki
Youichirou
Y
Yasuda
Shusuke
S
Kawanaka
Mayumi
M
Yogosawa
Shingo
S
Koyama
Makoto
M
Tantin
Dean
D
Sakai
Toshiyuki
T
D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D050811:Octamer Transcription Factor-1 / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050811:Octamer Transcription Factor-1; D012097:Repressor Proteins