CCAR2 negatively regulates nuclear receptor LXRalpha by competing with SIRT1 deacetylase.
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Sakurabashi A, Wada-Hiraike O, Hirano M, Fu H, Isono W, Fukuda T, Morita Y, Tanikawa M, Miyamoto Y, Oda K, Kawana K, Osuga Y, Fujii T
CCAR2 negatively regulates nuclear receptor LXRalpha by competing with SIRT1 deacetylase.
J Steroid Biochem Mol Biol. 2015 May;149:80-8. doi: 10.1016/j.jsbmb.2015.02.001. Epub 2015 Feb 3.
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- 25661920 [ View in PubMed]
- Abstract
Liver X receptors (LXRs) monitor endogenous sterol levels to maintain whole-body cholesterol levels and regulate inflammatory responses. Recent studies have demonstrated that LXRs may inhibit cellular proliferation, but the underlying mechanism remains unclear. Cell cycle and apoptosis regulator 2 (CCAR2), previously known as DBC1/KIAA1967, is a transcriptional regulator that regulates cellular proliferation and energy metabolism by inhibiting sirtuin 1 (SIRT1) deacetylase. Based on the findings that CCAR2 regulates several nuclear receptors, including the estrogen receptors and androgen receptor, we aimed to identify the underlying mechanism of CCAR2 regulation of LXRalpha. We found that CCAR2 formed a complex with LXRalpha in a ligand-independent manner in HepG2 cells, and in vitro pull-down assays, it revealed a direct interaction between the amino terminus of CCAR2 and the AF-2 domain of LXRalpha. Thereby, CCAR2 attenuates the ligand-dependent transcriptional activation function of LXRalpha. RNA interference-mediated depletion of endogenous CCAR2 potentiated the expression of the LXRalpha target genes ATP-binding cassette transporter A1 and G1, and the abrogation of CCAR2 resulted in decreased cellular proliferation. Moreover, competitive immunoprecipitation studies revealed that the LXRalpha downregulation involves the inhibition of SIRT1-LXRalpha complex formation. Therefore, these results clearly indicate a novel mechanism in which CCAR2 may regulate the transcriptional activation function of LXRalpha due to its specific inhibition of SIRT1 and serve to regulate cellular proliferation.