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Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1.

Publication ,  Journal Article
Schisler, JC; Fueger, PT; Babu, DA; Hohmeier, HE; Tessem, JS; Lu, D; Becker, TC; Naziruddin, B; Levy, M; Mirmira, RG; Newgard, CB
Published in: Mol Cell Biol
May 2008

The homeodomain transcription factor Nkx6.1 plays an important role in pancreatic islet beta-cell development, but its effects on adult beta-cell function, survival, and proliferation are not well understood. In the present study, we demonstrated that treatment of primary rat pancreatic islets with a cytomegalovirus promoter-driven recombinant adenovirus containing the Nkx6.1 cDNA (AdCMV-Nkx6.1) causes dramatic increases in [methyl-(3)H] thymidine and 5-bromo-2'-deoxyuridine (BrdU) incorporation and in the number of cells per islet relative to islets treated with a control adenovirus (AdCMV-betaGAL), whereas suppression of Nkx6.1 expression reduces thymidine incorporation. Immunocytochemical studies reveal that >80% of BrdU-positive cells in AdCMV-Nkx6.1-treated islets are beta cells. Microarray, real-time PCR, and immunoblot analyses reveal that overexpression of Nkx6.1 in rat islets causes concerted upregulation of a cadre of cell cycle control genes, including those encoding cyclins A, B, and E, and several regulatory kinases. Cyclin E is upregulated earlier than the other cyclins, and adenovirus-mediated overexpression of cyclin E is shown to be sufficient to activate islet cell proliferation. Moreover, chromatin immunoprecipitation assays demonstrate direct interaction of Nkx6.1 with the cyclin A2 and B1 genes. Overexpression of Nkx6.1 in rat islets caused a clear enhancement of glucose-stimulated insulin secretion (GSIS), whereas overexpression of Nkx6.1 in human islets caused an increase in the level of [(3)H]thymidine incorporation that was twice the control level, along with complete retention of GSIS. We conclude that Nkx6.1 is among the very rare factors capable of stimulating beta-cell replication with retention or enhancement of function, properties that may be exploitable for expansion of beta-cell mass in treatment of both major forms of diabetes.

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Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

May 2008

Volume

28

Issue

10

Start / End Page

3465 / 3476

Location

United States

Related Subject Headings

  • Tissue Culture Techniques
  • Recombinant Proteins
  • Rats
  • RNA, Small Interfering
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Models, Biological
  • Kinetics
  • Insulin-Secreting Cells
 

Citation

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Schisler, J. C., Fueger, P. T., Babu, D. A., Hohmeier, H. E., Tessem, J. S., Lu, D., … Newgard, C. B. (2008). Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1. Mol Cell Biol, 28(10), 3465–3476. https://doi.org/10.1128/MCB.01791-07
Schisler, Jonathan C., Patrick T. Fueger, Daniella A. Babu, Hans E. Hohmeier, Jeffery S. Tessem, Danhong Lu, Thomas C. Becker, et al. “Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1.Mol Cell Biol 28, no. 10 (May 2008): 3465–76. https://doi.org/10.1128/MCB.01791-07.
Schisler JC, Fueger PT, Babu DA, Hohmeier HE, Tessem JS, Lu D, et al. Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1. Mol Cell Biol. 2008 May;28(10):3465–76.
Schisler, Jonathan C., et al. “Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1.Mol Cell Biol, vol. 28, no. 10, May 2008, pp. 3465–76. Pubmed, doi:10.1128/MCB.01791-07.
Schisler JC, Fueger PT, Babu DA, Hohmeier HE, Tessem JS, Lu D, Becker TC, Naziruddin B, Levy M, Mirmira RG, Newgard CB. Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1. Mol Cell Biol. 2008 May;28(10):3465–3476.

Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

May 2008

Volume

28

Issue

10

Start / End Page

3465 / 3476

Location

United States

Related Subject Headings

  • Tissue Culture Techniques
  • Recombinant Proteins
  • Rats
  • RNA, Small Interfering
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Models, Biological
  • Kinetics
  • Insulin-Secreting Cells