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Vol. 13, Issue 10, 3720-3729, October 2002

Distinct Nongenomic Signal Transduction Pathways Controlled by 17-Estradiol Regulate DNA Synthesis and Cyclin D₁ Gene Transcription in HepG2 Cells

Maria Marino,^* Filippo Acconcia,^* Francesco Bresciani, Alessandro Weisz, and Anna Trentalance^*

 ^*Dipartimento di Biologia, Università "Roma Tre", I-00146 Rome, Italy; and  Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, I-80138 Napoli, Italy

Estrogens induce cell proliferation in target tissues by stimulating progression through the G1 phase of the cell cycle. Activation of cyclin D₁ gene expression is a critical feature of this hormonal action. The existence of rapid/nongenomic estradiol-regulated protein kinase C (PKC-) and extracellular signal-regulated kinase (ERK) signal transduction pathways, their cross talk, and role played in DNA synthesis and cyclin D₁ gene transcription have been studied herein in human hepatoma HepG2 cells. 17-Estradiol was found to rapidly activate PKC- 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 D₁ expression, and did not involve DNA binding by estrogen receptor. The results obtained with specific inhibitors indicated that PKC- pathway is necessary to mediate the estradiol-induced G1-S progression of HepG2 cells, but it does not exert any effect(s) on cyclin D₁ gene expression. On the contrary, ERK-2 cascade was strongly involved in both G1-S progression and cyclin D₁ gene transcription. Deletion of its activating protein-1 responsive element motif resulted in attenuation of cyclin D₁ promoter responsiveness to estrogen. These results indicate that estrogen-induced cyclin D₁ 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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Corresponding author. E-mail address: m.marino{at}uniroma3.it.

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Molecular Biology of the Cell
Vol. 13, 3720-3729, October 2002
Copyright © 2002 by The American Society for Cell Biology

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