Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells.
Human sirtuin 1 (SIRT1) is a NAD(+)-dependent deacetylase that participates in cell death/survival, senescence and metabolism. Although its substrates are well characterized, no direct regulators have been defined. Here, we show that SIRT1 associates with SKI-interacting protein (SKIP) and modulates its activity as a coactivator of retinoic acid receptor (RAR). Binding assays indicated that SKIP interacts with RAR in a RA-dependent manner, through a region that overlaps the binding site for SIRT1. SKIP augmented the transcriptional activation activity of RAR by cooperating with SRC-1, and SIRT1 suppressed SKIP/SRC-1-enhanced RAR transactivation activity. The suppression was dependent on the deacetylase activity of SIRT1 and was enhanced by a SIRT1 activator, resveratrol. In contrast, the suppression was relieved by SIRT1 knockdown, overexpression of SKIP and treatment with a SIRT1 inhibitor, splitomicin. Upon SKIP overexpression, the recruitment of SIRT1 to the endogenous RARbeta2 promoter was severely impaired, and SKIP was recruited to the promoter instead. Finally, resveratrol treatment inhibited RA-induced neuronal differentiation of P19 cells, accompanied by reductions in the neuronal marker nestin and a RAR target gene, RARbeta2. This inhibition was relieved by either knockdown of SIRT1 or overexpression of SKIP. These data suggest that SIRT1 and SKIP play reciprocal roles in the regulation of RAR activity, which is implicated in the regulation of RA-induced neuronal differentiation of P19 cells.
Kang
Moo-Rim
MR
Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea.
Lee
Sang-Wang
SW
Um
Elisa
E
Kang
Hyun Tae
HT
Hwang
Eun Seong
ES
Kim
Eun-Joo
EJ
Um
Soo-Jong
SJ
D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology*; D056918:Nuclear Receptor Coactivators / Q000378:metabolism / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D056564:Sirtuin 1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*
D056918:Nuclear Receptor Coactivators; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C111791:SNW1 protein, human; D014212:Tretinoin; C447939:SIRT1 protein, human; D056564:Sirtuin 1