Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo

Research output: Contribution to journalArticle

Abstract

Cdk2 was once believed to play an essential role in cell cycle progression, but cdk2-/- mice have minimal phenotypic abnormalities. In this study, we examined the role of cdk2 in hepatocyte proliferation, centrosome duplication and survival. Cdk2-/- hepatocytes underwent mitosis and had normal centrosome content after mitogen stimulation. Unlike wild-type cells, cdk2-/- liver cells failed to undergo centrosome overduplication in response to ectopic cyclin D1 expression. After mitogen stimulation in culture or partial hepatectomy in vivo, cdk2-/- hepatocytes demonstrated diminished proliferation. Cyclin D1 is a key mediator of cell cycle progression in hepatocytes, and transient expression of this protein is sufficient to promote robust proliferation of these cells in vivo. In cdk2-/- mice and animals treated with the cdk2 inhibitor seliciclib, cyclin D1 failed to induce hepatocyte cell cycle progression. Surprisingly, cdk2 ablation or inhibition led to massive hepatocyte and animal death following cyclin D1 transfection. In a transgenic model of chronic hepatic cyclin D1 expression, seliciclib induced hepatocyte injury and animal death, suggesting that cdk2 is required for survival of cyclin D1-expressing cells even in the absence of substantial proliferation. In conclusion, our studies demonstrate that cdk2 plays a role in liver regeneration. Furthermore, it is essential for centrosome overduplication, proliferation and survival of hepatocytes that aberrantly express cyclin D1 in vivo. These studies suggest that cdk2 may warrant further investigation as a target for therapy of liver tumors with constitutive cyclin D1 expression.

Details

Authors
  • Eric A. Hanse
  • Christopher J. Nelsen
  • Melissa M. Goggin
  • Chelsea K. Anttila
  • Lisa K. Mullany
  • Cyril Berthet
  • Philipp Kaldis
  • Gretchen S. Crary
  • Ryoko Kuriyama
  • Jeffrey H. Albrecht
External organisations
  • Hennepin County Medical Center
  • Minneapolis Medical Research Foundation
  • National Cancer Institute at Frederick
  • National Cancer Institute, USA
  • University of Minnesota system
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Apoptosis, cdk2, Centrosomes, Cyclin D1, Liver regeneration, Seliciclib
Original languageEnglish
Pages (from-to)2802-2809
Number of pages8
JournalCell Cycle
Volume8
Issue number17
Publication statusPublished - 2009 Sep 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes