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Cyclin D3 maintains growth-inhibitory activity of C/EBPalpha by stabilizing C/EBPalpha-cdk2 and C/EBPalpha-Brm

Guo-Li Wang1, Xiurong Shi, Elizabeth Salisbury

  • 1Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

Molecular and Cellular Biology
|March 16, 2006
PubMed

Insights

Cyclin D3-cdk4/cdk6 supports liver growth inhibition by phosphorylating C/EBPalpha, forming complexes that arrest proliferation. This mechanism is crucial in both young and old mice, with implications for liver regeneration and differentiation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • C/EBPalpha regulates liver proliferation by inhibiting cdk2 in young mice and via the C/EBPalpha-Brm complex in old mice.
  • Cyclin D3-cdk4/cdk6 kinases, typically promoting growth, are present in differentiated cells, suggesting alternative roles.

Purpose of the Study:

  • To investigate the role of cyclin D3-cdk4/cdk6 in supporting C/EBPalpha's growth-inhibitory functions in liver proliferation across different age groups.
  • To elucidate the mechanism by which cyclin D3-cdk4/cdk6 interacts with C/EBPalpha and influences proliferation-related complexes.

Main Methods:

  • In vitro and in vivo phosphorylation assays of C/EBPalpha by cyclin D3-cdk4/cdk6.
  • Analysis of C/EBPalpha-Brm and C/EBPalpha-cdk2 complex formation in differentiated liver and adipocyte cells.
  • Assessment of cyclin D3 and cdk4/cdk6 activity in aged mouse livers post-hepatectomy.

Main Results:

  • Cyclin D3-cdk4/cdk6 specifically phosphorylates C/EBPalpha at Ser193, stabilizing growth-inhibitory C/EBPalpha-cdk2 and C/EBPalpha-Brm complexes.
  • Increased cyclin D3 in old livers activates cdk4/cdk6, stabilizing C/EBPalpha-Brm and correlating with reduced proliferation.
  • Inhibition of cyclin D3 in 3T3-L1 cells blocks the formation of these growth-inhibitory complexes.

Conclusions:

  • Cyclin D3-cdk4/cdk6 plays a novel role in supporting the growth-inhibitory activity of C/EBPalpha through phosphorylation.
  • This mechanism contributes to the regulation of liver proliferation and cellular differentiation in both young and aged organisms.
  • Dysregulation of cyclin D3-cdk4/cdk6 activity may impair liver regeneration in older individuals.

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