Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27Kip1
Keiju Hiromura, … , James M. Roberts, Stuart J. Shankland
Keiju Hiromura, … , James M. Roberts, Stuart J. Shankland
Published March 1, 1999
Citation Information: J Clin Invest. 1999;103(5):597-604. https://doi.org/10.1172/JCI5461.
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Article

Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27Kip1

Abstract

Proliferation and apoptosis are increased in many types of inflammatory diseases. A role for the cyclin kinase inhibitor p27Kip1 (p27) in limiting proliferation has been shown. In this study, we show that p27–/– mesangial cells and fibroblasts have strikingly elevated rates of apoptosis, not proliferation, when deprived of growth factors. Apoptosis was rescued by restoration of p27 expression. Cyclin A–cyclin-dependent kinase 2 (CDK2) activity, but not cyclin E–CDK2 activity, was increased in serum-starved p27–/– cells, and decreasing CDK2 activity, either pharmacologically (Roscovitine) or by a dominant–negative mutant, inhibited apoptosis. Our results show that a new biological function for the CDK inhibitor p27 is protection of cells from apoptosis by constraining CDK2 activity. These results suggest that CDK inhibitors are necessary for coordinating the cell cycle and cell-death programs so that cell viability is maintained during exit from the cell cycle.

Authors

Keiju Hiromura, Jeffrey W. Pippin, Matthew L. Fero, James M. Roberts, Stuart J. Shankland

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Figure 8

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Proposed schema showing coordination of cell-cycle events by the CDK inh...
Proposed schema showing coordination of cell-cycle events by the CDK inhibitor p27. When grown in the presence of growth factors, reduced or absent p27 levels are associated with a coordinated and synchronous increase in cyclin E–CDK2 and cyclin A–CDK2 activity. This favors cell-cycle progression and proliferation. Under stress states such as growth factor deprivation, the loss of p27 is associated with an unconstrained increase in cyclin A–CDK2 activity, but not cyclin E–CDK2 activity. This unscheduled increase in CDK2 activity causes cell-cycle exit by apoptosis.