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

doi:10.1083/jcb.146.6.1255

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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 P21^cip1 Expression by Growth Factors and the Extracellular Matrix Reveals a Role for Transient ERK Activity in G1 Phase

Maria Elena Bottazzi^a, Xiaoyun Zhu^a, Ralph M. Böhmer^a, and Richard K. Assoian^a

^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 p21^cip1 by soluble mitogensand cell anchorage as well as the relationship between the expressionof p21^cip1 and activation of the ERK subfamily of MAP kinases.We find that p21^cip1 expression in G1 phase can be divided intotwo discrete phases: an initial induction that requires growthfactors and the activation of ERK, and then a subsequent declinethat is enhanced by cell anchorage in an ERK-independent manner.In contrast to the induction of cyclin D1, the induction ofp21^cip1 is mediated by transient ERK activity. Comparative studieswith wild-type and p21^cip1-null fibroblasts indicate that adhesion-dependentregulation of p21^cip1 is important for proper control of cyclinE–cdk2 activity. These data lead to a model in which mitogensand anchorage act in a parallel fashion to regulate G1 phaseexpression of p21^cip1. They also show that (a) growth factorsand growth factor/extracellular matrix cooperation can havedifferent roles in regulating G1 phase ERK activity and (b)both transient and sustained ERK signals have functionally significantroles in controlling cell cycle progression through G1 phase.

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

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

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 TuftsUniversity Medical School, Boston, MA 02111.

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