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-l (ET-1) i n primary astrocytes is dependent on activation of both extracellular signa l-regulated kinase (ERK)- and cytoskeleton (CSK)-dependent pathways. In thi s study, we evaluated the contribution of each of these pathways to the exp ression and activation of proteins mediating cell cycle progression. Our re sults suggest that ET-l-induced expression of cyclins D1 and D3 is dependen t on the ERK- and CSK-dependent pathways, respectively; moreover, a decreas e in the levels of the cyclin-dependent kinase inhibitor (CKI) p27 was obse rved as a consequence of ERK activation. Expression of both cyclins DI and D3 together with a decrease in the p27 levels are essential for retinoblast oma 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 leadi ng 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.