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Vol. 9, Issue 8, 2081-2092, August 1998
and§
* H. Lee Moffitt Cancer Center and Research Institute, Tampa,
Florida 33612; and Departments of
We report that cyclin D3/cdk4 kinase activity is regulated by
p27kip1 in BALB/c 3T3 cells. The association of
p27kip1 was found to result in inhibition of cyclin D3
activity as measured by immune complex kinase assays utilizing cyclin
D3-specific antibodies. The ternary p27kip1/cyclin D3/cdk4
complexes do exhibit kinase activity when measured in immune complex
kinase assays utilizing p27kip1-specific antibodies. The
association of p27kip1 with cyclin D3 was highest in
quiescent cells and declined upon mitogenic stimulation, concomitantly
with declines in the total level of p27kip1 protein. The
decline in this association could be elicited by PDGF treatment alone;
this was not sufficient, however, for activation of cyclin D3 activity,
which also required the presence of factors in platelet-poor plasma in
the culturing medium. Unlike cyclin D3 activity, which was detected
only in growing cells, p27kip1 kinase activity was present
throughout the cell cycle. Since we found that the p27kip1
activity was dependent on cyclin D3 and cdk4, we compared the substrate
specificity of the active ternary complex containing p27kip1 and the active cyclin D3 lacking
p27kip1 by tryptic phosphopeptide mapping of GST-Rb
phosphorylated in vitro and also by comparing the relative
phosphorylation activity toward a panel of peptide substrates. We found
that ternary p27kip1/cyclin D3/cdk4 complexes exhibited a
different specificity than the active binary cyclin D3/cdk4 complexes,
suggesting that p27kip1 has the capacity to both inhibit
cyclin D/cdk4 activity as well as to modulate cyclin D3/cdk4 activity
by altering its substrate preference.
Medical Microbiology
and Immunology and
Biochemistry and Molecular Biology,
University of South Florida, Tampa, Florida 33612
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