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Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors
Edited by Bruce M. Spiegelman, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, and approved February 24, 2014 (received for review November 7, 2013)

Significance
Loss of pancreatic islet β cells occurs in both major forms of diabetes, and strategies for restoring β cells are needed. The homeobox transcription factor NK6 homeobox 1 (Nkx6.1) activates β-cell proliferation and insulin secretion when overexpressed in pancreatic islets, but the molecular pathway involved in the proliferative response is unknown. We show that Nkx6.1 induces expression of orphan nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3), which stimulate proliferation via two mechanisms: (i) increased expression of the cell cycle inducers E2F transcription factor 1 and cyclin E1; and (ii) induction of anaphase-promoting complex elements, and degradation of the cell cycle inhibitor p21. These studies reveal a new bipartite pathway for activation of β-cell proliferation that could guide development of therapeutic strategies for diabetes.
Abstract
Loss of functional β-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 β-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates β-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 β-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in β-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 β-cell proliferation, suggesting several unique targets for expansion of functional β-cell mass.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: chris.newgard{at}duke.edu.
Author contributions: J.S.T., L.G.M., P.T., H.E.H., and C.B.N. designed research; J.S.T., L.C.C., M.A., D.L., M.V.J., S.B.S., and H.E.H. performed research; J.S.T., L.C.C., M.A., S.B.S., and P.T. contributed new reagents/analytic tools; J.S.T., L.G.M., H.E.H., and C.B.N. analyzed data; and J.S.T. and C.B.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE55079).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1320953111/-/DCSupplemental.