Negative regulation of Par-4 by oncogenic Ras is essential for cellular transformation.
Oncogenic variants of the cellular Ras protein are often associated with different types of human cancers. However, the mechanisms by which oncogenic Ras induces transformation are not fully established. Expression of the transcriptional repressor Par-4 was down-regulated by oncogenic Ras via the Raf-MEK-ERK pathway. Restoration of Par-4 levels by abrogation of the Raf-MEK-ERK pathway with the MEK-inhibitor PD98059 or by ectopic Par-4, that acted to inhibit ERK expression and activation, was sufficient to suppress oncogenic Ras-induced transformation. These findings identify Par-4 as a novel target that has to be down-modulated by oncogenic Ras for successful transformation.
Qiu
S G
SG
Department of Surgery, University of Kentucky, Lexington 40536, USA.
Krishnan
S
S
el-Guendy
N
N
Rangnekar
V M
VM
D016475:3T3 Cells; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; C101296:prostate apoptosis response-4 protein; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one