Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2.
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.
Yeom
Seon-Yong
SY
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Songpa-gu, Seoul 138-736, South Korea.
Kim
Geun Hyang
GH
Kim
Chan Hee
CH
Jung
Heun Don
HD
Kim
So-Yeon
SY
Park
Joong-Yeol
JY
Pak
Youngmi Kim
YK
Rhee
Dong-Kwon
DK
Kuang
Shao-Qing
SQ
Xu
Jianming
J
Han
Duck Jong
DJ
Song
Dae-Kyu
DK
Lee
Jae Woon
JW
Lee
Ki-Up
KU
Kim
Seung-Whan
SW
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
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