![]() ![]() PI 3-kinase activates its main downstream effector, the serine/threonine kinase Akt, which phosphorylates a variety of substrates that function to suppress apoptosis and promote progression through the cell cycle ( 6, 7, 18). The phosphatidylinositol (PI) 3-kinase pathway is a major regulator of mammalian cell survival and proliferation. These results show that PI 3-kinase regulation of mRNA stability, predominantly mediated by BRF1, plays a major role in regulating gene expression. Small interfering RNA (siRNA) experiments further showed that knockdown of BRF1 or KSRP, both ARE binding proteins (ARE-BPs) regulated by Akt, stabilized the mRNAs of a majority of the downregulated genes but that knockdown of ARE-BPs that are not regulated by PI 3-kinase did not affect degradation of these mRNAs. ![]() Analyses of β- globin-3′ untranslated region (UTR) fusion transcripts indicated that sequences within 3′ UTRs were the primary determinants of rapid mRNA decay. By blocking transcription with actinomycin D, we found that almost 40% of these genes were regulated via effects of PI 3-kinase on mRNA stability. We previously performed global expression analyses that identified a set of approximately 50 genes that were downregulated following inhibition of PI 3-kinase in proliferating T98G cells. Because steady-state levels of mRNA are regulated by degradation as well as transcription, we have investigated the importance of mRNA degradation in controlling gene expression downstream of PI 3-kinase. Control of gene expression by the phosphatidylinositol (PI) 3-kinase/Akt pathway plays an important role in mammalian cell proliferation and survival, and numerous transcription factors and genes regulated by PI 3-kinase signaling have been identified. ![]()
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