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J Biol Chem, Vol. 274, Issue 43, 31062-31067, October 22, 1999
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From the Platelet-derived growth factor (PDGF) stimulates
transcription of an immediate-early gene set in Balb/c 3T3 cells. One
cohort of these genes, typified by c-fos, is induced within
minutes following activation of PDGF receptors. A second cohort
responds to PDGF only after a significant time delay, although
induction is still a primary response to receptor activation as shown
by "superinduction" in the presence of the protein synthesis
inhibitor cycloheximide. PDGF-receptor activated signaling pathways for
the "slow" immediate-early genes are poorly resolved. Using
gain-of-function mutations together with small molecule inhibitors of
kinase activity, we show that activation of PI 3-kinase is both
necessary and sufficient for the induction of the prototype slow
immediate-early gene, monocyte chemoattractant-1 (MCP-1). Following
activation of PDGF receptors, MCP-1 mRNA does not begin to
accumulate for at least 90 min. However, only a brief (10 min) interval
of PI 3-kinase activity is required to trigger this delayed response.
The serine/threonine protein kinase, Akt/PKB, likely functions as a
downstream affector of PI 3-kinase for this induction.
Department of Microbiology and Molecular
Genetics, § Department of Pathology, Harvard Medical
School and the Division of Cancer Biology, Dana-Farber Cancer
Institute, Boston, Massachusetts 02115
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