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Mol Endocrinol. 2012 Sep;26(9):1590-602. doi: 10.1210/me.2012-1019. Epub 2012 Jul 13.

Overexpression of hepatocyte nuclear factor-4α initiates cell cycle entry, but is not sufficient to promote β-cell expansion in human islets.

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  • 1Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, 12-126 Translational Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-5156, USA.

Abstract

The transcription factor HNF4α (hepatocyte nuclear factor-4α) is required for increased β-cell proliferation during metabolic stress in vivo. We hypothesized that HNF4α could induce proliferation of human β-cells. We employed adenoviral-mediated overexpression of an isoform of HNF4α (HNF4α8) alone, or in combination with cyclin-dependent kinase (Cdk)6 and Cyclin D3, in human islets. Heightened HNF4α8 expression led to a 300-fold increase in the number of β-cells in early S-phase. When we overexpressed HNF4α8 together with Cdk6 and Cyclin D3, β-cell cycle entry was increased even further. However, the punctate manner of bromodeoxyuridine incorporation into HNF4α(High) β-cells indicated an uncoupling of the mechanisms that control the concise timing and execution of each cell cycle phase. Indeed, in HNF4α8-induced bromodeoxyuridine(+,punctate) β-cells we observed signs of dysregulated DNA synthesis, cell cycle arrest, and activation of a double stranded DNA damage-associated cell cycle checkpoint mechanism, leading to the initiation of loss of β-cell lineage fidelity. However, a substantial proportion of β-cells stimulated to enter the cell cycle by Cdk6 and Cyclin D3 alone also exhibited a DNA damage response. HNF4α8 is a mitogenic signal in the human β-cell but is not sufficient for completion of the cell cycle. The DNA damage response is a barrier to efficient β-cell proliferation in vitro, and we suggest its evaluation in all attempts to stimulate β-cell replication as an approach to diabetes treatment.

PMID:
22798294
[PubMed - indexed for MEDLINE]
PMCID:
PMC3434530
Free PMC Article

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