Phosphatidylinositol 3-kinase inhibitor wortmannin blocks mitogenic activation of the transferrin receptor gene promoter in late G1.
Expression of the transferrin receptor is necessary for cells to progress through S-phase. The transferrin receptor gene promoter is activated as a delayed event following growth factor stimulation of quiescent fibroblasts. Serum stimulation in the presence of vanadate leads to superactivation of the transferrin receptor promoter, suggesting a role for tyrosine phosphorylation. Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, a tyrosine kinase-regulated enzyme, blocks mitogen-dependent activation of the transferrin receptor promoter. Furthermore, wortmannin was able to block activation of this promoter when added several hours after serum stimulation of quiescent cells. This suggests that phosphatidylinositol 3-kinase may be required in mid to late G1 and that it is directly involved in a pathway leading to activation of the transferrin receptor promoter. This is further supported by the finding that the transferrin receptor promoter is much less responsive to mitogenic stimulation in cells that have been stably transfected with a dominant negative form of the phosphatidylinositol 3-kinase regulatory subunit. Activation of S6 kinase, an event known to be downstream of phosphatidylinositol 3-kinase activation, appears not to be involved in activation of the transferrin receptor promoter since no effect was observed by treatment of cells with rapamycin.
Miskimins
W K
WK
University of South Dakota School of Medicine, Department of Biochemistry and Molecular Biology, Vermillion 57069, USA.
King
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F
Miskimins
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D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011990:Receptors, Transferrin / Q000235:genetics*; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D008934:Mitogens; D011990:Receptors, Transferrin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin