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First published on October 25, 2006; DOI: 10.1124/mol.106.028639

0026-895X/07/7101-314-322$20.00
Mol Pharmacol 71:314-322, 2007

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RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells

Shujie Han, Stewart M. Knoepp, Mark A. Hallman, and Kathryn E. Meier

Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington (S.H., K.E.M.); and Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina (S.M.K., M.A.H., K.E.M.)

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to the tumor promoter phorbol 12-myristate 13-acetate (PMA). In sensitive EL4 cells, PMA causes robust Erk mitogen-activated protein kinase activation that results in growth arrest. In resistant cells, PMA induces minimal Erk activation, without growth arrest. PMA stimulates IL-2 production in sensitive, but not resistant, cells. The role of RasGRP1, a PMA-activated guanine nucleotide exchange factor for Ras, in EL4 phenotype was examined. Endogenous RasGRP1 protein is expressed at much higher levels in sensitive than in resistant cells. PMA-induced Ras activation is observed in sensitive cells but not in resistant cells lacking Ras-GRP1. PMA induces down-regulation of RasGRP1 protein in sensitive cells but increases RasGRP1 in resistant cells. Transfection of RasGRP1 into resistant cells enhances PMA-induced Erk activation. In the reverse experiment, introduction of small interfering RNA (siRNA) for RasGRP1 suppresses PMA-induced Ras and Erk activations in sensitive cells. Sensitive cells incubated with siRNA for RasGRP1 exhibit the PMA-resistant phenotype, in that they are able to proliferate in the presence of PMA and do not secrete IL-2 when stimulated with PMA. These studies indicate that the PMA-sensitive phenotype, as previously defined for the EL4 cell line, is conferred by endogenous expression of RasGRP1 protein.

Received July 6, 2006; accepted October 20, 2006

Address correspondence to: Kathryn E. Meier, Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164-6534. E-mail: kmeier{at}wsu.edu




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S. M. Knoepp, M. S. Chahal, Y. Xie, Z. Zhang, D. J. Brauner, M. A. Hallman, S. A. Robinson, S. Han, M. Imai, S. Tomlinson, et al.
Effects of Active and Inactive Phospholipase D2 on Signal Transduction, Adhesion, Migration, Invasion, and Metastasis in EL4 Lymphoma Cells
Mol. Pharmacol., September 1, 2008; 74(3): 574 - 584.
[Abstract] [Full Text] [PDF]


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