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© The Rockefeller University Press, 0021-9525/1999//1255 $5.00
The Journal of Cell Biology, Volume 146, Number 6, , 1999 1255-1264

Original Article

Regulation of P21cip1 Expression by Growth Factors and the Extracellular Matrix Reveals a Role for Transient ERK Activity in G1 Phase



Maria Elena Bottazzia, Xiaoyun Zhua, Ralph M. Böhmera, and Richard K. Assoiana

a Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084
Department of Pharmacology, University of Pennsylvania School of Medicine, 167 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084.(215) 573-5656(215) 898-7157

rka{at}pharm.med.upenn.edu

We have examined the regulation of p21cip1 by soluble mitogens and cell anchorage as well as the relationship between the expression of p21cip1 and activation of the ERK subfamily of MAP kinases. We find that p21cip1 expression in G1 phase can be divided into two discrete phases: an initial induction that requires growth factors and the activation of ERK, and then a subsequent decline that is enhanced by cell anchorage in an ERK-independent manner. In contrast to the induction of cyclin D1, the induction of p21cip1 is mediated by transient ERK activity. Comparative studies with wild-type and p21cip1-null fibroblasts indicate that adhesion-dependent regulation of p21cip1 is important for proper control of cyclin E–cdk2 activity. These data lead to a model in which mitogens and anchorage act in a parallel fashion to regulate G1 phase expression of p21cip1. They also show that (a) growth factors and growth factor/extracellular matrix cooperation can have different roles in regulating G1 phase ERK activity and (b) both transient and sustained ERK signals have functionally significant roles in controlling cell cycle progression through G1 phase.

Key Words: cell cycle • adhesion • ECM • MAP • kinase • cdk inhibitors

© 1999 The Rockefeller University Press

1.used in this paper: cdk, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; ECM, extracellular matrix; MEF, mouse embryo fibroblast; pRb, retinoblastoma protein; RTK, receptor tyrosine kinase

M.E. Bottazzi and X. Zhu are co-first authors on this paper.

X. Zhu's present address is Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33101.

R.M. Böhmer's present address is Division of Genetics, Department of Pediatrics, New England Medical Center and Tufts University Medical School, Boston, MA 02111.


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