Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity.
Human SIRT1 is an NAD+-dependent deacetylase protein that plays a role in cell death/survival, senescence, and endocrine signaling. While its substrates, including p53, have been well characterized, no direct regulators are known. We describe here a nuclear protein, active regulator of SIRT1 (AROS), which directly regulates SIRT1 function. AROS enhanced SIRT1-mediated deacetylation of p53 both in vitro and in vivo, and it inhibited p53-mediated transcriptional activity. AROS activity was abrogated by the SIRT1 inhibitors splitomicin and nicotinamide and by SIRT1 small interfering RNA (siRNA). In addition, AROS was unable to cooperate in p53 inactivation in an AROS-binding-defective SIRT1 mutant. Finally, knockdown of endogenous AROS using an antisense expression vector enhanced p21WAF1 expression and increased both the G0/G1 population and apoptosis in response to DNA damage, while AROS overexpression improved cell survival. To our knowledge, AROS is the first direct SIRT1 regulator to be identified that modulates p53-mediated growth regulation.
Kim
Eun-Joo
EJ
Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, Korea. ejk93@hanmail.net
Kho
Jeong-Hoon
JH
Kang
Moo-Rim
MR
Um
Soo-Jong
SJ
D000107:Acetylation; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D016193:G1 Phase / Q000235:genetics; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology; D009536:Niacinamide / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009281:Naphthalenes; D009687:Nuclear Proteins; D011753:Pyrones; D034741:RNA, Small Interfering; C524448:RPS19BP1 protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; C012589:trichostatin A; C444426:splitomicin; D005047:Etoposide; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins