Coupling of epidermal growth factor (EGF) with the antiproliferative activity of cAMP induces neuronal differentiation.
Nerve growth factor (NGF) functions as a progression factor with both mitogenic and antimitogenic activities. When PC12 cells are treated with NGF, they advance to the G1 stage of the cell cycle before they differentiate. The correlation between cessation of proliferation and differentiation suggests that the antimitotic activity of NGF may be obligatory for differentiation. Although epidermal growth factor- (EGF) and NGF-treated PC12 cells share several common properties, including activation of the mitogen-activated protein (MAP) kinase pathway and induction of immediate early genes, EGF is mitogenic for PC12 cells and does not normally stimulate differentiation. However, combinations of EGF and low levels of cAMP stimulate differentiation even though neither agent alone does (Mark, M. D., Liu, Y., Wong, S. T., Hinds, T. R., and Storm, D.R. (1995) J. Cell Biol. 130, 701-710). Since EGF is mitogenic for PC12 cells and differentiation may not occur until proliferation is inhibited, differentiation caused by cAMP and EGF may be due to the antiproliferative activity of cAMP. To test this hypothesis, we examined the effect of EGF or combinations of EGF and cAMP on PC12 cell proliferation. EGF alone stimulated proliferation of PC12 cells and increased the levels of several cell cycle progression factors including cdk2, cdk4, and cyclin B1. Cyclic AMP inhibited the EGF-stimulated increases in cell cycle progression factors as well as proliferation. Other antiproliferative agents including rapamycin, mimosine, and nitric oxide agonists also synergized with EGF to stimulate differentiation. These data indicate that the coupling of antiproliferative signals with EGF modifies the biological properties of EGF and converts it to a differentiating growth factor.
Mark
M D
MD
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Storm
D R
DR
D000818:Animals; D042846:CDC2-CDC28 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D019926:Cyclin B; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D016193:G1 Phase; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016716:PC12 Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats
C534701:Ccnb1 protein, rat; D019926:Cyclin B; D056744:Cyclin B1; D016213:Cyclins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D005576:Colforsin; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases