Journal article
Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors
Proceedings of the National Academy of Sciences - PNAS, Vol.111(14), pp.5242-5247
04/08/2014
DOI: 10.1073/pnas.1320953111
PMCID: PMC3986138
PMID: 24706823
Abstract
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.
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.
Details
- Title: Subtitle
- Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors
- Creators
- Jeffery S Tessem - Sarah W. Stedman Nutrition and Metabolism CenterLarry G Moss - Sarah W. Stedman Nutrition and Metabolism CenterLily C Chao - Howard Hughes Medical Institute andMichelle Arlotto - Sarah W. Stedman Nutrition and Metabolism CenterDanhong Lu - Sarah W. Stedman Nutrition and Metabolism CenterMette V Jensen - Sarah W. Stedman Nutrition and Metabolism CenterSamuel B Stephens - Sarah W. Stedman Nutrition and Metabolism CenterPeter Tontonoz - Howard Hughes Medical Institute andHans E Hohmeier - Sarah W. Stedman Nutrition and Metabolism CenterChristopher B Newgard - Sarah W. Stedman Nutrition and Metabolism Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(14), pp.5242-5247
- DOI
- 10.1073/pnas.1320953111
- PMID
- 24706823
- PMCID
- PMC3986138
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- Nr4a receptors regulate islet β-cell expansion
- Language
- English
- Date published
- 04/08/2014
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094516202771
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