Activation of the c-fos serum response element by phosphatidyl inositol 3-kinase and rho pathways in HeLa cells.
Many growth factors rapidly induce transcription of the c-fos proto-oncogene. We have investigated the pathways for induction of the c-fos promoter by serum and epidermal growth factor (EGF) in HeLa cells. Induction of the serum response element (SRE) of the c-fos promoter could be split into two parts, one involving the serum response factor-associated ternary complex factor (TCF) factors and the second mediated by core SRE sequences. Serum induction was mediated primarily by the core SRE, whereas EGF used both the TCF and core SRE pathways. Using activated and inhibitory signaling proteins, we found that phosphatidyl inositol 3-kinase (PI3K) and rho family members could mediate activation by serum. Activation by PI3K was mediated by core SRE sequences and was dependent upon rac and rho, suggesting a PI3K-to-rac-to-rho pathway for core SRE activation. The PI3K target Akt was also capable of activating the SRE but functioned through the TCF pathway, suggesting that Akt does not mediate the primary PI3K pathway to the SRE and that Akt is capable of activating TCF family members. Serum and EGF induction of the core SRE was partially inhibited by rho and PI3K inhibitors. The use of these inhibitors demonstrates the complexity of signaling pathways to the SRE and suggests that serum activates rho by PI3K-dependent and -independent pathways.
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
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Y
Wang
M
M
Falasca
J
J
Schlessinger
S
S
Malstrom
P
P
Tsichlis
J
J
Settleman
W
W
Hu
B
B
Lim
R
R
Prywes
D016475:3T3 Cells; D000818:Animals; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins
D004815:Epidermal Growth Factor; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; C000715470:MAS1 protein, human