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Vol. 12, Issue 12, 4066-4077, December 2001
and
*Department of Molecular Medicine, Cornell University College of
Veterinary Medicine, Ithaca, New York 14853; and
Integrin-mediated cell adhesion to the extracellular matrix
is required for normal cell growth. Cyclin D1 is a key regulator of
G1-to-S phase progression of the cell cycle. Our previous studies have
demonstrated that integrin signaling through focal adhesion kinase (FAK) plays a role in the regulation of cell cycle progression, which correlates with changes in the expression of cyclin D1 and the
cdk inhibitor, p21, induced by FAK. In this report, we first investigated the roles of both cyclin D1 and p21 in the regulation of
cell cycle progression by FAK. We found that overexpression of a
dominant-negative FAK mutant Department of Development and Molecular Biology and
Medicine, Albert Einstein College of Medicine, Bronx, New York 10461
C14 suppressed cell cycle progression in p21
/ cells as effectively as in the control
p21+/+ cells. Furthermore, we found that overexpression of
ectopic cyclin D1 could rescue cell cycle inhibition by C14. These
results suggested that cyclin D1, but not p21, was the primary
functional target of FAK signaling pathways in cell cycle regulation.
We then investigated the mechanisms underlying the regulation of cyclin
D1 expression by FAK signaling. Using Northern blotting and cyclin D1
promoter/luciferase assays, we showed that FAK signaling regulated
cyclin D1 expression at the transcriptional level. Using a series of
cyclin D1 promoter mutants in luciferase assays as well as
electrophoretic mobility shift assays (EMSA), we showed that the EtsB
binding site mediated cyclin D1 promoter regulation by FAK. Finally, we
showed that FAK regulation of cyclin D1 depends on
integrin-mediated cell adhesion and is likely through its
activation of the Erk signaling pathway. Together, these studies
demonstrate that transcriptional regulation of cyclin D1 by FAK
signaling pathways contributes to the regulation of cell cycle
progression in cell adhesion.
Corresponding author. E-mail address:
jg19{at}cornell.edu.
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