Nerve growth factor-induced growth arrest and induction of p21Cip1/WAF1 in NIH-3T3 cells expressing TrkA.
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 p21Cip1/WAF1 protein, an inhibitor of cyclin-dependent kinases, without affecting levels of p27KIP1 or p16INK4. Levels of p21Cip1/WAF1 remained elevated for at least 48 h following NGF addition. EGF had little effect on p21Cip1/WAF1 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 p21Cip1/WAF1 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 p21Cip1/WAF1 levels. The data also show that distinct signals are generated by TrkA versus the EGF receptor in NIH-3T3 cells.
Decker
S J
SJ
Parke-Davis Pharmaceuticals, Ann Arbor, Michigan 48106, USA.
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D003001:Cloning, Molecular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA