Ha-ras oncogene-induced Stat3 phosphorylation enhances oncogenicity of the cell.
The ras oncogene needs a second factor to induce transformation and tumorigenicity of the cell. In this study, we show that mouse fibroblast 7-4-Stat3C cells overexpressing both Ha-ras(val12) oncogene and active-form Stat3 (Stat3C) showed higher colony formation in soft agar and xenograft tumor growth in BALB/c mice. Further studies show that both serine-727 and tyrosine-705 of Stat3 were phosphorylated while Ha-ras was overexpressed. Interleukin-6 (IL-6)-induced phosphorylation of tyrosine-705 and serine-727, as well as DNA-binding and transcriptional activity of Stat3 were further enhanced by Ha-ras overexpression. In addition, overexpression of Stat3C in 7-4-Stat3C cells prevented the cells from morphological change and apoptosis triggered by the Ha-ras oncogene under serum-depleted conditions. We demonstrate that Ha-ras and Stat3 acting together synergistically induce Stat3 phosphorylation at serine-727 phosphorylation and cyclin D1 expression and further enhance transformation and tumorigenicity of the cell. Ha-ras-induced Stat3 phosphorylation at serine-727 plays a pivotal role in transcriptional activation of cyclin D1 and suppression of cell apoptosis. The effect of Ha-ras on Stat3 phosphorylation at serine-727 was also detected in human bladder (T24) and lung (H460) cancer cells. Stat3 phosphorylation at serine-727 is important in Ras-related tumorigenesis.
Yeh
Hsuan-Heng
HH
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
Giri
Raghavaraju
R
Chang
Tsuey-Yu
TY
Chou
Cheng-Yang
CY
Su
Wu-Chou
WC
Liu
Hsiao-Sheng
HS
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics*; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects*; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D012694:Serine