| First Author | Tessem JS | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 14 | Pages | 5242-7 |
| PubMed ID | 24706823 | Mgi Jnum | J:208626 |
| Mgi Id | MGI:5563845 | Doi | 10.1073/pnas.1320953111 |
| Citation | Tessem JS, et al. (2014) Nkx6.1 regulates islet beta-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proc Natl Acad Sci U S A 111(14):5242-7 |
| abstractText | Loss of functional beta-cell mass is a hallmark of type 1 and type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor NK6 homeobox 1 (Nkx6.1) in rat pancreatic islets induces beta-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates beta-cell expansion has not been defined. Here, we demonstrate that Nkx6.1 induces expression of the nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3) orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated beta-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in beta-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F transcription factor 1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including ubiquitin-conjugating enzyme E2C, resulting in degradation of the cell cycle inhibitor p21. These studies identify a unique bipartite pathway for activation of beta-cell proliferation, suggesting several unique targets for expansion of functional beta-cell mass. |
