Nkx6.1 regulates islet ?-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.

ABSTRACT: Loss of functional ?-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 ?-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates ?-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 ?-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in ?-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 ?-cell proliferation, suggesting several unique targets for expansion of functional ?-cell mass.

SUBMITTER: Tessem JS 

PROVIDER: S-EPMC3986138 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature