CDK2 translational down-regulation during endothelial senescence

Exp Cell Res. 2005 Jul 1;307(1):118-30. doi: 10.1016/j.yexcr.2005.03.025. Epub 2005 Apr 21.


Here we report for the first time that loss of CDK2 activity, by translational inhibition and through CDK2 inhibition by p21(Cip1/Waf1), may be responsible for endothelial senescence. We show that expression of dominant-negative p53 extends human umbilical vein endothelial cell (HUVEC) lifespan past senescence. HUVEC expressing telomerase can completely bypass senescence and become immortal (i-HUVEC). Surprisingly, early passage i-HUVEC, like senescent HUVEC, express high levels of the CDK inhibitors p16(INK4a) and p21(Cip1/Waf1). Expression of p16(INK4a) can persist for over 280 population doublings, while p21(Cip1/Waf1) expression was eventually lost in five of six i-HUVEC lines. Senescent HUVEC contain undetectable CDK2 activity, which results from a dramatic reduction of CDK2 protein levels and inhibition of remaining CDK2 by p21(Cip1/Waf1). The decreased CDK2 levels in senescent HUVEC are not due to decreased transcription or protein stability; rather, CDK2 translation declines during senescence. Bypass of endothelial senescence by telomerase entails the restoration of CDK2 translation and activity. These results suggest that p16(INK4a) does not play a role in endothelial senescence. Rather, CDK2 translational down-regulation may be a key regulatory event in replicative senescence of endothelial cells. Understanding the mechanisms regulating endothelial senescence will be critical in determining the role of endothelial senescence in tumor growth.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • CDC2-CDC28 Kinases / analysis
  • CDC2-CDC28 Kinases / genetics
  • CDC2-CDC28 Kinases / metabolism*
  • Cell Culture Techniques
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Transformed
  • Cells, Cultured
  • Cellular Senescence*
  • Clone Cells
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p16 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21
  • Down-Regulation*
  • Endothelium, Vascular / cytology
  • Genetic Vectors
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Kinetics
  • Mitosis
  • Models, Biological
  • Precipitin Tests
  • Retroviridae / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Telomerase / metabolism
  • Umbilical Veins / cytology


  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Green Fluorescent Proteins
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Telomerase