| First Author | Zhao F | Year | 2012 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 303 |
| Issue | 1 | Pages | E132-43 |
| PubMed ID | 22550067 | Mgi Jnum | J:187188 |
| Mgi Id | MGI:5435649 | Doi | 10.1152/ajpendo.00074.2012 |
| Citation | Zhao F, et al. (2012) Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 beta-cells. Am J Physiol Endocrinol Metab 303(1):E132-43 |
| abstractText | We demonstrated previously that the activation of ALK7 (activin receptor-like kinase-7), a member of the type I receptor serine/threonine kinases of the TGF-beta superfamily, resulted in increased apoptosis and reduced proliferation through suppression of Akt signaling and the activation of Smad2-dependent signaling pathway in pancreatic beta-cells. Here, we show that Nodal activates ALK7 signaling and regulates beta-cell apoptosis. We detected Nodal expression in the clonal beta-cell lines and rodent islet beta-cells. Induction of beta-cell apoptosis by treatment with high glucose, palmitate, or cytokines significantly increased Nodal expression in clonal INS-1 beta-cells and isolated rat islets. The stimuli induced upregulation of Nodal expression levels were associated with elevation of ALK7 protein and enhanced phosphorylated Smad3 protein. Nodal treatment or overexpression of Nodal dose- or time-dependently increased active caspase-3 levels in INS-1 cells. Nodal-induced apoptosis was associated with decreased Akt phosphorylation and reduced expression level of X-linked inhibitor of apoptosis (XIAP). Remarkably, overexpression of XIAP or constitutively active Akt, or ablation of Smad2/3 activity partially blocked Nodal-induced apoptosis. Furthermore, siRNA-mediated ALK7 knockdown significantly attenuated Nodal-induced apoptosis of INS-1 cells. We suggest that Nodal-induced apoptosis in beta-cells is mediated through ALK7 signaling involving the activation of Smad2/3-caspase-3 and the suppression of Akt and XIAP pathways and that Nodal may exert its biological effects on the modulation of beta-cell survival and beta-cell mass in an autocrine fashion. |
