HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27
| Autor: | Kyle B. Kener, Aaron H. Leifer, Amanda Haines, Jeffery S. Tessem, Courtney J. Smith, Patrick T. Fueger, Kavan H. Hess, Angelina Hernandez-Carretero, Michelle Arlotto, Lanair A. Lett, Carrie Draney, Matthew C. Austin, Talon J. Aitken |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male animal structures Cyclin D Down-Regulation Histone Deacetylase 1 Biochemistry Gene Expression Regulation Enzymologic 03 medical and health sciences 0302 clinical medicine Insulin-Secreting Cells E2F1 Animals Humans Rats Wistar Cyclin B1 Molecular Biology Cells Cultured Cell Proliferation biology Cell growth Chemistry Cell Biology Cell cycle Cell biology Rats 030104 developmental biology 030220 oncology & carcinogenesis embryonic structures biology.protein Cyclin-dependent kinase 6 CDKN1B Cyclin A2 Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | The Biochemical journal. 475(24) |
| ISSN: | 1470-8728 |
| Popis: | The homeobox transcription factor Nkx6.1 is sufficient to increase functional β-cell mass, where functional β-cell mass refers to the combination of β-cell proliferation, glucose-stimulated insulin secretion (GSIS) and β-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional β-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase β-cell proliferation in primary rat islets and the INS-1 832/13 β-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing β-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 β-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional β-cell mass. |
| Databáze: | OpenAIRE |
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