RESUMEN
A commonality between type 1 and type 2 diabetes is the decline in functional ß-cell mass. The transcription factor Nkx6.1 regulates ß-cell development and is integral for proper ß-cell function. We have previously demonstrated that Nkx6.1 depends on c-Fos mediated upregulation and the nuclear hormone receptors Nr4a1 and Nr4a3 to increase ß-cell insulin secretion, survival, and replication. Here, we demonstrate that Nkx6.1 overexpression results in upregulation of the bZip transcription factor CEBPA and that CEBPA expression is independent of c-Fos regulation. In turn, CEBPA overexpression is sufficient to enhance INS-1 832/13 ß-cell and primary rat islet proliferation. CEBPA overexpression also increases the survival of ß-cells treated with thapsigargin. We demonstrate that increased survival in response to ER stress corresponds with changes in expression of various genes involved in the unfolded protein response, including decreased Ire1a expression. These data show that CEBPA is sufficient to enhance functional ß-cell mass by increasing ß-cell proliferation and modulating the unfolded protein response.
RESUMEN
The homeobox transcription factor Nkx6.1 is sufficient to increase functional ß-cell mass, where functional ß-cell mass refers to the combination of ß-cell proliferation, glucose-stimulated insulin secretion (GSIS) and ß-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional ß-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase ß-cell proliferation in primary rat islets and the INS-1 832/13 ß-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing ß-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated ß-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional ß-cell mass.
