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

Sebastian Rieck, Jia Zhang, Zhaoyu Li, Chengyang Liu, Ali Naji, Karen K. Takane, Nathalie M. Fiaschi-Taesch, Andrew F. Stewart, Jake A. Kushner, Klaus H. Kaestner

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39 Scopus citations

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 HNF4αHigh 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.

Original languageEnglish (US)
Pages (from-to)1590-1602
Number of pages13
JournalMolecular Endocrinology
Volume26
Issue number9
DOIs
StatePublished - Sep 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Rieck, S., Zhang, J., Li, Z., Liu, C., Naji, A., Takane, K. K., Fiaschi-Taesch, N. M., Stewart, A. F., Kushner, J. A., & Kaestner, K. H. (2012). Overexpression of hepatocyte nuclear factor-4α initiates cell cycle entry, but is not sufficient to promote β-cell expansion in human islets. Molecular Endocrinology, 26(9), 1590-1602. https://doi.org/10.1210/me.2012-1019