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J. Biol. Chem., Vol. 279, Issue 10, 8911-8918, March 5, 2004

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Phosphatidylinositol 3-Kinase and mTOR Signaling Pathways Regulate RNA Polymerase I Transcription in Response to IGF-1 and Nutrients^*

Martyn J. James and Joost C. B. M. Zomerdijk

From the Division of Gene Regulation and Expression, Wellcome Trust Biocentre, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom

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.

Received for publication, July 17, 2003 , and in revised form, December 17, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Medical Research Council Ph.D. studentship. Current address: Institute of Biotechnology, Viikki Biocenter, P. O. Box 56, FIN-00014 University of Helsinki, Finland.

A Wellcome Trust Senior Research Fellow in the Basic Biomedical Sciences. To whom correspondence should be addressed. Tel.: 44-1382-344242; Fax: 44-1382-348072; E-mail: j.zomerdijk{at}dundee.ac.uk.

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