title: Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2.
abstract: Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic beta-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/- mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/- mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/- islets. These results suggest that ASC-2 regulates insulin secretion and beta-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Songpa-gu, Seoul 138-736, South Korea.
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Yeom
authors.forename: Geun Hyang
authors.initials: GH
authors.lastname: Kim
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Heun Don
authors.initials: HD
authors.lastname: Jung
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
authors.forename: Shao-Qing
authors.initials: SQ
authors.lastname: Kuang
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Duck Jong
authors.initials: DJ
authors.lastname: Han
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Song
authors.forename: Jae Woon
authors.initials: JW
authors.lastname: Lee
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D056918:Nuclear Receptor Coactivators; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C405683:Ncoa6 protein, mouse; C486560:Ncoa6 protein, rat; D056918:Nuclear Receptor Coactivators; D012333:RNA, Messenger; D004247:DNA; D005947:Glucose