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.
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December 2018
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In this issue, Arnal et al. investigate the molecular basis of substrate regiospecificity and processivity of an exemplar bacterial Glycoside Hydrolase Family 74 endo-xyloglucanase. The cover image shows a protein structure with a uniquely large oligosaccharide complex. The enzyme was taken from a wheat rhizome bacterium. The image was supplied by Harry Brumer and Peter Stogios.
Research Article|
December 19 2018
HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27
Carrie Draney;
Carrie Draney
*
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Matthew C. Austin;
Matthew C. Austin
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Aaron H. Leifer;
Aaron H. Leifer
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Courtney J. Smith;
Courtney J. Smith
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Kyle B. Kener;
Kyle B. Kener
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Talon J. Aitken;
Talon J. Aitken
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Kavan H. Hess;
Kavan H. Hess
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Amanda C. Haines;
Amanda C. Haines
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
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Elle Lett;
Elle Lett
†
2Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, U.S.A.
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Angelina Hernandez-Carretero;
Angelina Hernandez-Carretero
3Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA 91010, U.S.A.
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Patrick T. Fueger;
Patrick T. Fueger
3Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA 91010, U.S.A.
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Michelle Arlotto;
Michelle Arlotto
2Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, U.S.A.
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Jeffery S. Tessem
1Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.
Correspondence: Jeffery S. Tessem (jeffery_tessem@byu.edu)
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Publisher: Portland Press Ltd
Received:
June 14 2018
Revision Received:
October 12 2018
Accepted:
October 14 2018
Accepted Manuscript online:
October 15 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (24): 3997–4010.
Article history
Received:
June 14 2018
Revision Received:
October 12 2018
Accepted:
October 14 2018
Accepted Manuscript online:
October 15 2018
Citation
Carrie Draney, Matthew C. Austin, Aaron H. Leifer, Courtney J. Smith, Kyle B. Kener, Talon J. Aitken, Kavan H. Hess, Amanda C. Haines, Elle Lett, Angelina Hernandez-Carretero, Patrick T. Fueger, Michelle Arlotto, Jeffery S. Tessem; HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27. Biochem J 21 December 2018; 475 (24): 3997–4010. doi: https://doi.org/10.1042/BCJ20180465
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