D1 dopamine receptor regulation of the levels of the cell-cycle-controlling proteins, cyclin D, P27 and Raf-1, in cerebral cortical precursor cells is mediated through cAMP-independent pathways.
Previously, we demonstrated that dopamine D1 receptor (D1R) agonists inhibit epidermal growth factor (EGF)-induced passage of mouse fetal cerebral cortical precursor cells from the G1 phase to the S phase of the cell cycle. Here, we report that this action of D1R agonists may involve regulation of cyclin D, and P27, which respectively promote and suppress the G1 to S transition. Furthermore, regulation of Raf-1, a component of the receptor tyrosine kinase mitogen-activated protein kinase pathway engaged in the mitogenic activity of EGF, may also be involved. Specifically, levels of cyclin D and Raf-1 decrease, whereas those of P27 first increase and then decrease in a dose-dependent fashion in response to the D1R agonist, SKF38393. This agonist also promotes Raf-1 phosphorylation on serine 338 residue, suggesting increased activation of this protein. Only the latter effect can be blocked by adenylyl cyclase (AC) and cAMP-dependent protein kinase A (PKA) inhibitors, and mimicked by agonists of the cAMP signaling pathway. Another D1R agonist, SKF83959, which stimulates phospholipase Cbeta (PLCbeta) but not AC, reduces levels of Raf-1 and cyclin D similar to SKF38393. However, we detected only down-regulation of P27 by this agonist. Additionally, the concentration-dependent patterns of both SKF38393- and SKF83959-induced alterations in the levels of P27 closely resemble the effects of these ligands on the levels of the D1R-PLCbeta-associated second-messenger cascades linker, calcyon. These findings suggest that D1R-induced suppression of the cell cycle progression in EGF-supported fetal cortical precursor cells represents a net effect of competing cell cycle promoting and inhibiting molecular changes, which involve cyclin D, P27 and Raf-1. The data also show that cAMP second messenger cascade is not engaged in the D1R-induced regulation of the levels of these three proteins. Such regulation probably involves PLCbeta-associated pathways.
Zhang
Ling
L
Department of Biomedical Sciences, University of Maryland, Baltimore, MD 21201, USA.
Bai
Jie
J
Undie
Ashiwel S
AS
Bergson
Clare
C
Lidow
Michael S
MS
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D000242:Cyclic AMP / Q000378:metabolism; D056741:Cyclin D; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D018491:Dopamine Agonists; D008565:Membrane Proteins; D017447:Receptors, Dopamine D1; D025521:Tumor Suppressor Proteins; C405464:calcyon; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D000242:Cyclic AMP; D019908:Proto-Oncogene Proteins c-raf