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Submitted on December 15, 2006
Revised on March 6, 2008
Accepted on March 19, 2008
*Departments 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;
Departments of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
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 is known to play a role in myocyte differentiation in cultured cells. Herein, NGF induced cyclin D1 promoter, mRNA and protein expression via the p21RAS pathway. Antisense- or siRNA 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/MAPK pathway, and chemical inhibitors, demonstrated NGF induction of cyclin D1 involved cooperative interactions of ERK, p38 and PI3K pathways downsteam of p21RAS. NGF induced the cyclin D1 promoter thought via Sp1, NF-
B and CRE/ATF sites. NGF induction via Sp1 involved the formation of an 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)