Identification of senescence-associated genes and their networks under oxidative stress by the analysis of Bach1.
Cellular senescence is induced in response to DNA damage, caused by genotoxic stresses, including oxidative stress, and serves as a barrier against malignant transformation. Tumor-suppressor protein p53 induces genes critical for implementing cellular senescence. However, the identities of p53 target genes and other regulators that achieve senescence under oxidative stress remain to be elucidated. Effector genes for oxidative stress-induced cellular senescence were sought, based on the fact that transcription factor Bach1 inhibits this response by impeding the transcriptional activity of p53. pRb became hypophosphorylated more rapidly in Bach1-deficient MEFs than in wild-type cells, suggesting that pRb activation was involved in their senescence. Bach1-deficient MEFs bypassed the senescence state when the expression of a subset of p53 target genes, including p21, Pai1, Noxa, and Perp, was simultaneously reduced by using RNAi. Combined knockdown of p21 and pRb resulted in vigorous re-proliferation. These results suggest that oxidative stress-induced cellular senescence is registered by multiple p53 target genes, which arrest proliferation redundantly, in part by activating pRb. Our elucidations contrast with previous reports describing monopolistic regulations of senescence by single p53 target genes.
Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, Japan.
Kazushige
K
Ota
Yoshihiro
Y
Dohi
Andrey
A
Brydun
Ayako
A
Nakanome
Sadayoshi
S
Ito
Kazuhiko
K
Igarashi
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D053263:Gene Regulatory Networks; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics*; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051547:Heme Oxygenase-1