Abstract
The mouse Y1 adrenocortical tumor cell line is highly responsive to FGF2-(Fibroblast Growth Factor 2) and possesses amplified and over-expressed c-Ki-ras proto-oncogene. We previously reported that this genetic lesion leads to high constitutive levels of activation of the c-Ki-Ras-GTP-->PI3K-->Akt signaling pathway (Forti et al. 2002). On the other hand, activation levels of another important pathway downstream of c-Ki-Ras-GTP, namely, Raf-->MEK-->ERK, remain strictly dependent on FGF2 stimulation (Rocha et al. 2003). Here we show that, first, FGF2 transiently up-regulates the c-Ki-Ras-GTP-->PI3K-->Akt pathway, in spite of its high basal levels. Second, c-Ki-Ras-GTP transient up-regulation likely underlies activation of the ERK1/2 pathway by FGF2. Third, c-Ki-Ras-GTP high basal levels suppress activation of the c-H-Ras onco-protein. But, Y1 cells, expressing dominant negative mutant RasN17, display a rapid and transient up-regulation of c-H-Ras-GTP upon FGF2 treatment. Elucidation of FGF2-signaling pathways in Y1 tumor cells can uncover new targets for drug development of interest in cancer therapy.
Highlights
Fifty years ago, Pavan and collaborators (Breuer and Pavan 1955, Ficq and Pavan 1957) described differential replication of DNA in the giant polytene chromosomes of salivary glands from the diptera Rhynchosciara americana, a phenomenon thereafter denominated DNA puffing
Amplification of oncogenes became progressively recognized as an important part of the genetic bases underlying both carcinogenesis and resistance of tumor cells to drug therapy (Schwab 1999). c-Ki-Ras was the first oncogene reported amplified, over-expressed and located in abnormal chromosomes of the mouse Y1 adrenocortical tumor cell line (Schwab et al 1983)
In this paper we report on the earliest activation steps of FGF2 signaling, namely, activation of Ras onco-proteins and of both ERK and PI3K/Akt pathways
Summary
Pavan and collaborators (Breuer and Pavan 1955, Ficq and Pavan 1957) described differential replication of DNA in the giant polytene chromosomes of salivary glands from the diptera Rhynchosciara americana, a phenomenon thereafter denominated DNA puffing. In Y1 adrenocortical cells c-Ki-ras oncogene amplification (Schwab et al 1983, Kimura and Armelin 1988) causes over-expression of both c-Kiras mRNA and protein, leading to high basal levels of c-Ki-Ras-GTP (Forti et al 2002) and, partial deregulation of cell cycle control.
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