Skip to main content
release_alert
Welcome to the new Scholars 3.0! Read about new features and let us know what you think.
cancel
Journal cover image

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

Publication ,  Journal Article
Tessem, JS; Moss, LG; Chao, LC; Arlotto, M; Lu, D; Jensen, MV; Stephens, SB; Tontonoz, P; Hohmeier, HE; Newgard, CB
Published in: Proc Natl Acad Sci U S A
April 8, 2014

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 8, 2014

Volume

111

Issue

14

Start / End Page

5242 / 5247

Location

United States

Related Subject Headings

  • Up-Regulation
  • Ubiquitin-Conjugating Enzymes
  • Rats, Wistar
  • Rats
  • RNA, Messenger
  • Oligonucleotide Array Sequence Analysis
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Nerve Tissue Proteins
  • Mice, Knockout
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tessem, J. S., Moss, L. G., Chao, L. C., Arlotto, M., Lu, D., Jensen, M. V., … Newgard, C. B. (2014). Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proc Natl Acad Sci U S A, 111(14), 5242–5247. https://doi.org/10.1073/pnas.1320953111
Tessem, Jeffery S., Larry G. Moss, Lily C. Chao, Michelle Arlotto, Danhong Lu, Mette V. Jensen, Samuel B. Stephens, Peter Tontonoz, Hans E. Hohmeier, and Christopher B. Newgard. “Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.Proc Natl Acad Sci U S A 111, no. 14 (April 8, 2014): 5242–47. https://doi.org/10.1073/pnas.1320953111.
Tessem JS, Moss LG, Chao LC, Arlotto M, Lu D, Jensen MV, et al. Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5242–7.
Tessem, Jeffery S., et al. “Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.Proc Natl Acad Sci U S A, vol. 111, no. 14, Apr. 2014, pp. 5242–47. Pubmed, doi:10.1073/pnas.1320953111.
Tessem JS, Moss LG, Chao LC, Arlotto M, Lu D, Jensen MV, Stephens SB, Tontonoz P, Hohmeier HE, Newgard CB. Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5242–5247.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 8, 2014

Volume

111

Issue

14

Start / End Page

5242 / 5247

Location

United States

Related Subject Headings

  • Up-Regulation
  • Ubiquitin-Conjugating Enzymes
  • Rats, Wistar
  • Rats
  • RNA, Messenger
  • Oligonucleotide Array Sequence Analysis
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Nerve Tissue Proteins
  • Mice, Knockout
  • Male