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1 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
2 Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
3 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA
* To whom correspondence should be addressed. E-mail: choudhuryg{at}uthscsa.edu.
Epidermal growth factor (EGF) is a potent mitogen for mesangial cells. The mechanism by which EGF induces DNA synthesis is not precisely understood. We investigated the role of phosphatidylinositol (PI) 3 kinase in regulating mitogenesis. EGF increased PI 3 kinase activity resulting in stimulation of PDK-1 and Akt kinase activities. Blocking of PI 3 kinase activity using Ly 294002 or adenoviral expression of PTEN, which dephosphorylates PI 3,4,5-tris-phosphate (PIP3) and thus inactivates PI 3 kinase signaling, significantly inhibits EGF-induced DNA synthesis. Expression of dominant negative Akt kinase, however, had no effect on DNA synthesis. But it inhibited EGF-induced phosphorylation of FoxO3a transcription factor, thus demonstrating its functional consequences. These data indicate that EGF increases the DNA synthesis in a PI 3 kinase-dependent but Akt-independent manner. In addition to activating PI 3 kinase signaling, EGF increased Erk1/2 MAPK activity, leading to transcriptional activation of its nuclear target Elk-1, and resulting in c-fos expression. Inhibition of MAPK activity by MEK inhibitor U0126 abolished EGF-induced DNA synthesis. Since EGF activates PI 3 kinase, which also regulates DNA synthesis, the effect of PI 3 kinase on MAPK activity was also examined. Inhibition of PI 3 kinase signaling blocked EGF-induced MAPK activity as well as Elk-1 dependent reporter transcription and c-fos gene transcription. To further determine the mechanism of EGF-induced DNA synthesis, we investigated the effect of EGF on the cyclin-dependent kinase inhibitor p27Kip1. EGF reduced the expression of p27Kip1. Inhibition of PI 3 kinase action or MAPK activity abolished the reduction in p27Kip1 expression induced by EGF. These data provide the evidence that a linear signal transduction pathway involving PI 3 kinase-dependent MAPK regulates EGF-induced DNA synthesis in mesangial cells by regulating c-fos and p27Kip1 expression.
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