Essential role of p38gamma in K-Ras transformation independent of phosphorylation. J Biol Chem 2005 Jun 24;280(25):23910-7
Date
04/27/2005Pubmed ID
15851477Pubmed Central ID
PMC1224721DOI
10.1074/jbc.M500699200Scopus ID
2-s2.0-21244490119 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
MAPK cascades play the critical role in regulating Ras oncogene activity by phosphorylation-dependent mechanisms. Whereas the ERK MAPK pathway is required for Ras transformation, our previous works established that the p38 activity is inhibitory to Ras signaling in both experimental and ras-mutated cancer cells (Chen, G., Hitomi, M., Han, J., and Stacey, D. W. (2000) J. Biol. Chem. 275, 38973-38980; Qi, X., Tang, J., Pramanik, R., Schultz, R. M., Shirasawa, S., Sasazuki, T., Han, J., and Chen, G. (2004) J. Biol. Chem., 279, 22138-22144). Here we report that K-Ras activated p38gamma, a p38 MAPK family member, by inducing its expression without increasing its phosphorylation and that depletion of induced p38gamma suppressed Ras transformation in rat intestinal epithelial cells. This p38gamma activity contrasts with that of its family member, p38alpha, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. Mechanistic analyses showed that unphosphorylated p38gamma may promote Ras transformation through an increased complex formation with ERK proteins. Significantly, functional p38gamma protein was expressed only in K-ras-mutated human colon cancer cells, and p38gamma transcripts were ubiquitously increased in a set of primary human colon cancer tissues. These studies thus demonstrate the essential role of p38gamma in K-Ras transformation independent of phosphorylation, and elevated p38gamma may serve as a novel diagnostic marker and therapeutic target for human colon cancer.
Author List
Tang J, Qi X, Mercola D, Han J, Chen GAuthors
Guan Chen PhD, MD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinXiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBase Sequence
Cell Line, Transformed
DNA Primers
Epithelial Cells
Genes, ras
Phosphorylation
Rats
p38 Mitogen-Activated Protein Kinases
