Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.
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.
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology, and Department of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, NC 27704.
Jeffery S
JS
Tessem
Larry G
LG
Moss
Lily C
LC
Chao
Michelle
M
Arlotto
Danhong
D
Lu
Mette V
MV
Jensen
Samuel B
SB
Stephens
Peter
P
Tontonoz
Hans E
HE
Hohmeier
Christopher B
CB
Newgard
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C491327:Nkx6-1 protein, rat; C539820:Nr4a1 protein, rat; C091333:Nr4a3 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D044763:Ubiquitin-Conjugating Enzymes