SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation

Recent evidence indicates that phosphatidylinositol 3-kinase (PI3K) is a ce ntral regulator of mitosis, apoptosis and oncogenesis, Nevertheless, the me chanisms by which PI3K regulates proliferation are not well characterized. Mitogens stimulate entry into the cell cycle by inducing the expression of immediate early genes (IEGs) that in turn trigger the expression of G(1) cy clins, Here we describe a novel PI3K-regulated transcriptional cascade that is critical for mitogen regulation of the IEG, c-fos, We show that PI3K ac tivates gene expression by transactivating SRF-dependent transcription inde pendently of the previously described Rho and ETS TCF pathways. PI3K-stimul ated cell cycle progression requires transactivation of SRF and expression of dominant-negative PI3K blocks mitogen-stimulated cell cycle progression. Furthermore, dominant-interfering SRF mutants attenuate mitogen-stimulated cell cycle progression, but are without effect on MEK-stimulated cell cycl e entry. Moreover, expression of constitutively active SRP is sufficient fo r cell cycle entry. Thus, we delineate a novel SRF-dependent mitogenic casc ade that is critical for PI3K- and growth factor-mediated cell cycle progre ssion.