Oncogenic Ras-induced morphologic change is through MEK/ERK signaling pathway to downregulate Stat3 at a posttranslational level in NIH3T3 cells.
Ras is a key regulator of the MAP kinase-signaling cascade and may cause morphologic change of Ras-transformed cells. Signal transducer and activator of transcription 3 (Stat3) can be activated by cytokine stimulation. In this study, we unravel that Ha-ras(V12) overexpression can downregulate the expression of Stat3 protein at a posttranslational level in NIH3T3 cells. Furthermore, we demonstrate that Stat3 expression downregulated by Ha-ras(V12) overexpression is through proteosome degradation and not through a mTOR/p70S6K-related signaling pathway. The suppression of Stat3 accompanied by the morphologic change induced by Ha-ras(V12) was through mitogen extracellular kinase (MEK)/extracellular-regulated kinase (ERK) signaling pathway. Microtubule disruption is involved in Ha-ras(V12)-induced morphologic change, which could be reversed by overexpression of Stat3. Taken together, we are the first to demonstrate that Stat3 protein plays a critical role in Ha-ras(V12)-induced morphologic change. Oncogenic Ras-triggered morphologic change is through the activation of MEK/ERK to posttranslationally downregulate Stat3 expression. Our finding may shed light on developing novel therapeutic strategies against Ras-related tumorigenesis.
Yeh
Hsuan-Heng
HH
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
Wu
Chin-Han
CH
Giri
Raghavaraju
R
Kato
Ken
K
Kohno
Kimitoshi
K
Izumi
Hiroto
H
Chou
Cheng-Yang
CY
Su
Wu-Chou
WC
Liu
Hsiao-Sheng
HS
D000818:Animals; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases
D050796:STAT3 Transcription Factor; D011494:Protein Kinases; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras)