Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 13, Issue 10, Pages 3720-3729Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E02-03-0153
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Estrogens induce cell proliferation in target tissues by stimulating progression through the G1 phase of the cell cycle. Activation of cyclin D-1 gene expression is a critical feature of this hormonal action. The existence of rapid/nongenomic estradiol-regulated protein kinase C (PKC-alpha) and extracellular signal-regulated kinase (ERK) signal transduction pathways, their cross talk, and role played in DNA synthesis and cyclin D-1 gene transcription have been studied herein in human hepatoma HepG2 cells. 17beta-Estradiol was found to rapidly activate PKC-alpha translocation and ERK-2/mitogen-activated protein kinase phosphorylation. in this cell line. These actions were independent of each other, preceding the increase of thymidine incorporation into DNA and cyclin D-1 expression, and did not involve DNA binding by estrogen receptor. The results obtained with specific inhibitors indicated that PKC-alpha pathway is necessary to mediate the estradiol-induced G1-S progression of HepG2 cells, but it does not exert any effect(s) on cyclin D-1 gene expression. On the contrary, ERK-2 cascade was strongly involved in both G1-S progression and cyclin D-1 gene transcription. Deletion of its activating protein-1 responsive element motif resulted in attenuation of cyclin D-1 promoter responsiveness to estrogen. These results indicate that estrogen-induced cyclin D-1 transcription can occur in HepG2 cells independently of the transcriptional activity of estrogen receptor, sustaining the pivotal role played by nongenomic pathways of estrogen action in hormone-induced proliferation.
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