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Vol. 19, Issue 6, 2566-2578, June 2008

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Nerve Growth Factor Regulation of Cyclin D1 in PC12 Cells through a p21^RAS Extracellular Signal-regulated Kinase Pathway Requires Cooperative Interactions between Sp1 and Nuclear Factor-B

Francesco Marampon^*,, Mathew C. Casimiro^*,, Maofu Fu^*, Michael J. Powell^*, Vladimir M. Popov^*, Jaime Lindsay^*, Bianca M. Zani, Carmela Ciccarelli, Genichi Watanabe, Richard J. Lee, and Richard G. Pestell^*

*Department of Cancer Biology and Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy; and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461

Submitted December 15, 2006; Revised March 6, 2008; Accepted March 19, 2008
Monitoring Editor: William Tansey

The PC12 pheochromocytoma cell line responds to nerve growth factor (NGF) by exiting from the cell cycle and differentiating to induce extending neurites. Cyclin D1 is an important regulator of G1/S phase cell cycle progression, and it is known to play a role in myocyte differentiation in cultured cells. Herein, NGF induced cyclin D1 promoter, mRNA, and protein expression via the p21^RAS pathway. Antisense- or small interfering RNA to cyclin D1 abolished NGF-mediated neurite outgrowth, demonstrating the essential role of cyclin D1 in NGF-mediated differentiation. Expression vectors encoding mutants of the Ras/mitogen-activated protein kinase pathway, and chemical inhibitors, demonstrated NGF induction of cyclin D1 involved cooperative interactions of extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase pathways downstream of p21^RAS. NGF induced the cyclin D1 promoter via Sp1, nuclear factor-B, and cAMP-response element/activated transcription factor sites. NGF induction via Sp1 involved the formation of a Sp1/p50/p107 complex. Cyclin D1 induction by NGF governs differentiation and neurite outgrowth in PC12 cells.

These authors contributed equally to this work.

Address correspondence to: Richard G. Pestell (richard.pestell{at}jefferson.edu).