Raf-independent deregulation of p38 and JNK mitogen-activated protein kinases are critical for Ras transformation.
Activated Ras, but not Raf, causes transformation of RIE-1 epithelial cells, supporting the importance of Raf-independent pathways in mediating Ras transformation. The p38 and JNK mitogen-activated protein kinase cascades are activated by Ras via Raf-independent effector function. Therefore, we determined whether p38 and JNK activation are involved in Ras transformation of RIE-1 epithelial cells. Rather surprisingly, we found that pharmacologic inhibition of p38, together with Raf activation of ERK, was sufficient to mimic the morphologic and growth transformation caused by oncogenic Ras. p38 inhibition together with ERK activation also caused the same alterations in cyclin D1 and p21(CIP1) expression caused by Ras and induced an autocrine growth factor loop important for transformation. Finally, in contrast to p38, we found that JNK activation promoted Ras transformation, and that Ras deregulation of p38 and JNK was not mediated by activation of the Rac small GTPase. We conclude that a key action of Raf-independent effector pathways important for Ras transformation may involve inhibition of p38 and activation of JNK.
Pruitt
Kevin
K
University of North Carolina, Lineberger Comprehensive Cancer Center, Department of Pharmacology, Chapel Hill, North Carolina 27599, USA.
Pruitt
Wendy M
WM
Bilter
Graham K
GK
Westwick
John K
JK
Der
Channing J
CJ
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003001:Cloning, Molecular; D017077:Culture Media, Conditioned; D019938:Cyclin D1 / Q000235:genetics; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras; D007093:Imidazoles / Q000494:pharmacology; D007413:Intestinal Mucosa; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D017077:Culture Media, Conditioned; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D019938:Cyclin D1; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one