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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/F145    most recent 00092.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Xing, J. Articles by Zhuang, S. PubMed PubMed Citation Articles by Xing, J. Articles by Zhuang, S.

Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms

¹Department of Medicine, Brown University School of Medicine, Rhode Island Hospital, Providence, Rhode Island; ²Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; and ³Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina

Submitted 22 February 2008 ; accepted in final form 17 April 2008

Our recent studies showed that Src family kinases (SFKs) are important mediators of proliferation in renal proximal tubular cells (RPTC). In this study, we elucidate the signaling mechanisms that mediate SFK regulation of cell proliferation and cycle protein expression, and identify the SFK member responsible for these responses in a mouse RPTC line. Akt, a target of phosphoinositide-3-kinase (PI3K), and ERK1/2 were constitutively phosphorylated in RPTC cultured in the presence of serum. While treatment of cells with PP1, a specific SFK inhibitor, completely blocked phosphorylation of ERK1/2 and Akt, only inhibition of PI3K/Akt resulted in decreased RPTC proliferation. Incubation of cells with PP1 decreased cyclin D1 expression, decreased p27 and p57 phosphorylation, and increased p27 and p57 expression, two cyclin-dependent kinase inhibitors. Inhibition of the PI3K pathway decreased expression of cyclin D1 without altering expression of p27 and p57. In contrast, PP1 and PI3K inhibition had no effect on cyclin E and p21. Although RPTC expressed Src, Fyn, and Lyn, only siRNA-mediated knockdown of Src decreased RPTC proliferation, decreased cyclin D1 expression, and increased p27 and p57 expression. These data reveal that Src is a crucial mediator of RPTC proliferation and Src-mediated proliferation is associated with PI3K-dependent upregulation of cyclin D1 and PI3K-independent downregulation of p27 and p57.

signal transduction processes; tissue regeneration