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Vol. 11, Issue 6, 2117-2130, June 2000

Density-dependent Growth Inhibition of Fibroblasts Ectopically Expressing p27kip1

Xiaohong Zhang,Dagger Walker Wharton,dagger Marcia Donovan, Domenico Coppola,*dagger Rhonda Croxton,Dagger W. Douglas Cress,Dagger and W. J. PledgerDagger §

Molecular Oncology Program and  *Clinical Investigation Program, H. Lee Moffitt Cancer Center, and Departments of  dagger Pathology and  Dagger Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa, Florida 33612

The cyclin/cyclin-dependent kinase (cdk) inhibitor p27kip1 is thought to be responsible for the onset and maintenance of the quiescent state. It is possible, however, that cells respond differently to p27kip1 in different conditions, and using a BALB/c-3T3 cell line (termed p27-47) that inducibly expresses high levels of this protein, we show that the effect of p27kip1 on cell cycle traverse is determined by cell density. We found that ectopic expression of p27kip1 blocked the proliferation of p27-47 cells at high density but had little effect on the growth of cells at low density whether exponentially cycling or stimulated from quiescence. Regardless of cell density, the activities of cdk4 and cdk2 were markedly repressed by p27kip1 expression, as was the cdk4-dependent dissociation of E2F4/p130 complexes. Infection of cells with SV40, a DNA tumor virus known to abrogate formation of p130- and Rb-containing complexes, allowed dense cultures to proliferate in the presence of supraphysiological amounts of p27kip1 but did not stimulate cell cycle traverse when cultures were cotreated with the potent cdk2 inhibitor roscovitine. Our data suggest that residual levels of cyclin/cdk activity persist in p27kip1-expressing p27-47 cells and are sufficient for the growth of low-density cells and of high-density cells infected with SV40, and that effective disruption of p130 and/or Rb complexes is obligatory for the proliferation of high-density cultures.

§ Corresponding author.

Molecular Biology of the Cell
Vol. 11, 2117-2130, June 2000
Copyright © 2000 by The American Society for Cell Biology


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