Moreover, knockdown of NR4A1 and NR4A3 impedes the production of ATP and ultimately inhibits glucose-stimulated insulin secretion.
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Ray et al., "[beta]-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion," American Journal of Physiology Endocrinology and Metabolism, vol.
Here we report that Cdk5r1 is upregulated by the orphan nuclear receptors Nr4a1 and Nr4a3 in primary rat islets.
Adenoviruses expressing Nkx6.1, Nr4a1, Nr4a3, and GFP have been described elsewhere [10, 34-39].
Previously published microarray data were queried for genes upregulated by Nr4a1 and Nr4a3 48 hours after adenoviral transduction that were not regulated by Nkx6.1 at 24, 48, or 96 hours after adenoviral transduction time points.
Cdk5r1 Is Induced by Nr4a1 and Nr4a3. We have previously shown that overexpression of the [beta]-cell transcription factor Nkx6.1 is sufficient to induce [beta]-cell proliferation .
Among these genes, the Cdk5 ligand Cdk5r1 was found to be upregulated 1.7-fold by Nr4a1 and Nr4a3 but not upregulated by Nkx6.1.
While untreated islets, islets expressing GFP, and islets expressing Nkx6.1 had no increased Cdk5r1 mRNA levels, islets transduced with Nr4a1 or Nr4a3 had 13.5- and 10.1-fold increase, respectively (Figure 2(a)).
We have previously shown that the Nkx6.1 mediated [beta]-cell proliferation pathway is dependent on the orphan nuclear receptors Nr4a1 and Nr4a3 [10,11].
Our data demonstrate that overexpression of Nr4a1 or Nr4a3 is sufficient to induce expression of Cdk5r1 and that overexpression of Cdk5r1 is sufficient to induce [beta]-cell proliferation.
In conclusion, our findings demonstrate that the orphan nuclear receptors Nr4a1 and Nr4a3 induce expression of the novel cell cycle activator Cdk5r1 independent of the Nkx6.1 signaling pathway.