title: CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase.
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 LXRα. We found that CCAR2 formed a complex with LXRα 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 LXRα. Thereby, CCAR2 attenuates the ligand-dependent transcriptional activation function of LXRα. RNA interference-mediated depletion of endogenous CCAR2 potentiated the expression of the LXRα 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 LXRα downregulation involves the inhibition of SIRT1-LXRα complex formation. Therefore, these results clearly indicate a novel mechanism in which CCAR2 may regulate the transcriptional activation function of LXRα due to its specific inhibition of SIRT1 and serve to regulate cellular proliferation.
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Ayako
authors: A
authors: Sakurabashi
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: osamuwh-tky@umin.ac.jp.
authors: Osamu
authors: O
authors: Wada-Hiraike
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Mana
authors: M
authors: Hirano
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Houju
authors: H
authors: Fu
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Wataru
authors: W
authors: Isono
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Tomohiko
authors: T
authors: Fukuda
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Yoshihiro
authors: Y
authors: Morita
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Michihiro
authors: M
authors: Tanikawa
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Yuichiro
authors: Y
authors: Miyamoto
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Katsutoshi
authors: K
authors: Oda
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Kei
authors: K
authors: Kawana
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Yutaka
authors: Y
authors: Osuga
authors: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Tomoyuki
authors: T
authors: Fujii
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors; D061986:MCF-7 Cells; D057093:Orphan Nuclear Receptors / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D056564:Sirtuin 1 / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: CCAR2; Competition; LXR; Proliferation; Repression; Transcription