Phosphatidylinositol 3-kinase and mTOR signaling pathways regulate RNA polymerase I transcription in response to IGF-1 and nutrients.
Regulation of ribosomal RNA gene transcription by RNA polymerase I (Pol I) is fundamental to ribosome biogenesis and therefore protein translation capacity and cell growth, yet little is known of the key signaling cascades involved. We show here that insulin-like growth factor-1 (IGF-1)-induced Pol I transcription in HEK293 cells is entirely dependent on phosphatidylinositol 3-kinase (PI3K) activity and, additionally, is modulated by the mammalian target of rapamycin (mTOR), which coordinates Pol I transcription with the availability of amino acids. The mitogen-activated protein kinase (MAPK) pathway is weakly stimulated by IGF-1 in these cells and partly contributes to Pol I transcription regulation. Activation of Pol I transcription by IGF-1 results from enhancement of the activity of the Pol I transcription machinery and increased occupancy by SL1 of the endogenous tandemly repeated ribosomal promoters in vivo. The inputs from PI3K, mTOR, and MAPK pathways converge to direct appropriate rRNA gene expression by Pol I in the nucleolus of mammalian cells in response to environmental cues, such as growth factors and nutrients.
James
Martyn J
MJ
Division of Gene Regulation and Expression, Wellcome Trust Biocentre, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
Zomerdijk
Joost C B M
JC
D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism*; D012318:RNA Polymerase I / Q000096:biosynthesis* / Q000235:genetics; D020038:RNA, Spliced Leader; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic / Q000187:drug effects
D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D012318:RNA Polymerase I; D020038:RNA, Spliced Leader; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human