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Nr4a1 and Nr4a3 upregulate cell cycle genes upregulated in the Nkx6.1 beta-cell proliferation pathway


ABSTRACT: Loss of functional beta-cell mass is a hallmark of Type 1 and Type 2 diabetes, and methods for restoring these cells are needed. Nkx6.1 induces beta-cell proliferation, 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 Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Overexpression of the Nr4a receptors results in increased expression of key cell cycle inducers E2F1 and cyclin E1. Furthermore, Nr4a receptors induce components of the anaphase-promoting complex, including Ube2c. We set up a microarray using primary rat islets that were left untreated or transduced with adenoviruses overexpressing GFP, Nr4a1 or Nr4a3 for 48 h.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Larry Moss 

PROVIDER: E-GEOD-55078 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Tessem Jeffery S JS   Moss Larry G LG   Chao Lily C LC   Arlotto Michelle M   Lu Danhong D   Jensen Mette V MV   Stephens Samuel B SB   Tontonoz Peter P   Hohmeier Hans E HE   Newgard Christopher B CB  

Proceedings of the National Academy of Sciences of the United States of America 20140324 14


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  ...[more]

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