Nerve Growth Factor-induced Growth Arrest and Induction of p21
in NIH-3T3 Cells Expressing TrkA (*)
- From the From Parke-Davis Pharmaceuticals, Ann Arbor, Michigan 48106 and the Department of Microbiology, University of Michigan School of Medicine, Ann Arbor, Michigan 48104
- § To whom correspondence should be addressed: Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Rd., Ann Arbor, MI 48106. Tel.: 313-998-5945; Fax: 313-996-5668; deckers{at}aa.wl.com.
Abstract
Treatment of NIH-3T3 cells expressing human TrkA with nerve growth factor (NGF) resulted in a rapid cessation of growth. Cells
stopped dividing within 24 h of NGF treatment and failed to divide as long as NGF was present, accumulating in the G1 stage of the cell cycle. NGF caused a prolonged activation of mitogen-activated protein kinase relative to EGF. NGF treatment
of cells greatly increased levels of the p21
protein, an inhibitor of cyclin-dependent kinases, without affecting levels of p27
or p16
. Levels of p21
remained elevated for at least 48 h following NGF addition. EGF had little effect on p21
expression in the same parental cells expressing the human EGF receptor. NGF treatment of cells completely inhibited the
activity of the cyclin-dependent protein kinases CDK2 and CDK4. Inhibition correlated with a 10-20-fold increase in the amount
of p21
complexed with CDK2 and CDK4. Levels of CDK2 and CDK4 were decreased following NGF treatment of cells; however, levels of
cyclin E and cyclin D were increased. These data indicate that NGF can induce cell cycle arrest of NIH-3T3, perhaps through
modulation of p21
levels. The data also show that distinct signals are generated by TrkA versus the EGF receptor in NIH-3T3 cells.
Footnotes
-
↵* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- NGF
-
nerve growth factor
- EGF
-
epidermal growth factor
- EGFR
-
EGF receptor
- MAP
-
mitogen-activated protein
- CDK
-
cell cycle-dependent kinase.
-
- Received October 4, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
