Differential regulation of cyclin D1 and D3 expression in the control of astrocyte proliferation induced by endothelin-1.
We have previously shown that the mitogenic effect of endothelin-1 (ET-1) in primary astrocytes is dependent on activation of both extracellular signal-regulated kinase (ERK)- and cytoskeleton (CSK)-dependent pathways. In this study, we evaluated the contribution of each of these pathways to the expression and activation of proteins mediating cell cycle progression. Our results suggest that ET-1-induced expression of cyclins D1 and D3 is dependent on the ERK- and CSK-dependent pathways, respectively; moreover, a decrease in the levels of the cyclin-dependent kinase inhibitor (CKI) p27 was observed as a consequence of ERK activation. Expression of both cyclins D1 and D3 together with a decrease in the p27 levels are essential for retinoblastoma protein (pRB) phosphorylation and cyclin A expression. Furthermore, the molecular events responsible for cell-cell contact inhibition of astrocyte proliferation were found to be independent of the mitogenic pathways leading to D-type cyclin expression. Cell growth arrest in confluent astrocytes was found to be correlated with increased expression of CKI p21, resulting in inhibition of D-type cyclin-associated pRB phosphorylation and cyclin A expression. Taken together, these results indicate that cyclins D1 and D3, which constitute the key mediators of the proliferative response of primary astrocytes to ET-1, are regulated by distinct signaling pathways.
Teixeira
A
A
Institut Cochin de Génétique Moléculaire, CNRS UPR 0415, Université Paris VII, France.
Chaverot
N
N
Strosberg
A D
AD
Cazaubon
S
S
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism*; D003599:Cytoskeleton / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology*; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C534698:Ccnd3 protein, rat; C493958:Cdkn1a protein, rat; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019332:Endothelin-1; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases