PT  - JOURNAL ARTICLE
AU  - Shujie Han
AU  - Stewart M. Knoepp
AU  - Mark A. Hallman
AU  - Kathryn E. Meier
TI  - RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells
AID  - 10.1124/mol.106.028639
DP  - 2007 Jan 01
TA  - Molecular Pharmacology
PG  - 314--322
VI  - 71
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/71/1/314.short
4100  - http://molpharm.aspetjournals.org/content/71/1/314.full
SO  - Mol Pharmacol2007 Jan 01; 71
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics