Regulation of Insulin Secretion and β-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 ␤-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 ␤-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.Type 2 diabetes is the most common form of diabetes and is a disorder of glucose homeostasis resulting from insulin resistance and relative insulin deficiency (52). Insulin secretion is affected by metabolic signals and transcription factors that are necessary for proper differentiation and growth of various types of pancreatic islet cells (10). The main intracellular signals for insulin secretion derive from glucose metabolism. Glucose metabolism generates oscillations in the ATP/ADP ratio, which lead to the opening and closing of ATP-sensitive K ϩ channels and produce subsequent oscillations in membrane potential, cytoplasmic calcium concentration, and insulin release (7).Studies of human mutations and knockout mice revealed several transcription factors that play crucial roles in pancreatic development, such as PDX-1 (also known as IPF-1) (21), Nkx2.2 (50), Pax4 (47), neurogenin3 (15), and NeuroD (40). The significance of transcription factors in pancreatic development was further reinforced by the analysis of mutations in patients with maturity-onset diabetes of the young (MODY).MODY is a monogenic type of diabetes characterized by early onset, autosomal dominant inheritance and impaired insulin secretion. Although the MODY2 gene encodes a glucokinase specific to the liver and ␤-cells (3), the remaining five MODY genes encode the transcription factors hepatic nuclear factor

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

“…Activating signal cointegrator-2 (Asc2), a transcriptional coactivator of nuclear receptors has also been shown to be involved in glucose sensitive insulin secretion and the maintenance of β cell mass (Yeom et al 2006). The mechanisms are unclear, although there is evidence that the liver X receptor (LXR), which is also involved in glucose sensing in β cells (Efanov et al 2004), and the MODY1 gene Hnf4α might be involved.…”

Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice

“…Disruption of both NCoA6 alleles in mice results in embryonic lethality due to defective development of the placenta, heart, and liver (3,18,23,51). Disruption of one NCoA6 allele in mice accelerates polyomavirus middle-T-antigen-induced mammary tumorigenesis, reduces insulin secretion, and slightly affects postnatal growth (23,43,47). In addition, specific deletion of the NCoA6 gene in mouse mammary epithelial cells decreases mammary ductal growth regulated by estrogen and partially impairs milk synthesis (33).…”

Regulation of hepatic insulin sensitivity by activating signal co-integrator-2

“…In a previous study we found that ASC-2 + / − mice greater than 20week-old had a higher plasma glucose level than wild-type mice of the same age [27]. However, we recently recognized that plasma glucose levels were not significantly different in young (10-weekold) ASC-2 + / − and wild-type mice (Supplementary Figure S1 at http://www.BiochemJ.org/bj/447/bj4470437add.htm).…”

“…Islet isolation was accomplished by collagenase digestion and differential centrifugation through Ficoll gradients using a previously described procedure [27]. After isolation, islets were incubated overnight in RPMI 1640 medium (11 mM glucose) and supplemented with 100 IU/ml penicillin, 100 μg/ml streptomycin and 10 % (v/v) FBS (fetal bovine serum).…”

“…In previous studies, we demonstrated that ASC-2 acts as a crucial transcriptional co-activator in insulin secretion and maintenance of pancreatic β-cell mass [27]. The ASC-2 gene is amplified and overexpressed in human cancers, and the protein stimulates transactivation by many members of the nuclear receptor superfamily, as well as AP-1 (activator protein 1), NF-κB, CREB, p53 and numerous other transcription factors.…”