Aurora Kinase A is critical for the Nkx6.1 mediated ß-cell proliferation pathway.

ABSTRACT

Type 1 and type 2 diabetes are ultimately characterized by depleted ß-cell mass. Characterization of the molecular pathways that control ß-cell proliferation could be harnessed to restore these cells. The homeobox ß-cell transcription factor Nkx6.1 induces ß-cell proliferation by activating the orphan nuclear receptors Nr4a1 and Nr4a3. Here, we demonstrate that Nkx6.1 localizes to the promoter of the mitotic kinase AURKA (Aurora Kinase A) and induces its expression. Adenovirus mediated overexpression of AURKA is sufficient to induce proliferation in primary rat islets while maintaining glucose stimulated insulin secretion. Furthermore, AURKA is necessary for Nkx6.1 mediated ß-cell proliferation as demonstrated by shRNA mediated knock down and pharmacological inhibition of AURKA kinase activity. AURKA preferentially induces DNA replication in ß-cells as measured by BrdU incorporation, and enhances the rate of histone H3 phosphorylation in primary ß-cells, demonstrating that AURKA induces the replicative and mitotic cell cycle phases in rat ß-cells. Finally, overexpression of AURKA results in phosphorylation of the cell cycle regulator p53, which targets p53 for degradation and permits cell cycle progression. These studies define a pathway by which AURKA upregulation by Nkx6.1 results in phosphorylation and degradation of p53, thus removing a key inhibitory factor and permitting engagement of the ß-cell proliferation pathway.