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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...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Oxford University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817470/ https://www.ncbi.nlm.nih.gov/pubmed/19934264 http://dx.doi.org/10.1093/nar/gkp1056 |
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author | Kang, Moo-Rim Lee, Sang-Wang Um, Elisa Kang, Hyun Tae Hwang, Eun Seong Kim, Eun-Joo Um, Soo-Jong |
author_facet | Kang, Moo-Rim Lee, Sang-Wang Um, Elisa Kang, Hyun Tae Hwang, Eun Seong Kim, Eun-Joo Um, Soo-Jong |
author_sort | Kang, Moo-Rim |
collection | PubMed |
description | 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 RARβ2 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, RARβ2. 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. |
format | Text |
id | pubmed-2817470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28174702010-02-08 Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells Kang, Moo-Rim Lee, Sang-Wang Um, Elisa Kang, Hyun Tae Hwang, Eun Seong Kim, Eun-Joo Um, Soo-Jong Nucleic Acids Res Gene Regulation, Chromatin and Epigenetics 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 RARβ2 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, RARβ2. 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. Oxford University Press 2010-01 2009-11-24 /pmc/articles/PMC2817470/ /pubmed/19934264 http://dx.doi.org/10.1093/nar/gkp1056 Text en © The Author(s) 2009. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.5/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Gene Regulation, Chromatin and Epigenetics Kang, Moo-Rim Lee, Sang-Wang Um, Elisa Kang, Hyun Tae Hwang, Eun Seong Kim, Eun-Joo Um, Soo-Jong Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells |
title | Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells |
title_full | Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells |
title_fullStr | Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells |
title_full_unstemmed | Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells |
title_short | Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells |
title_sort | reciprocal roles of sirt1 and skip in the regulation of rar activity: implication in the retinoic acid-induced neuronal differentiation of p19 cells |
topic | Gene Regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817470/ https://www.ncbi.nlm.nih.gov/pubmed/19934264 http://dx.doi.org/10.1093/nar/gkp1056 |
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