Abstract
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.
Highlights
Cell growth and proliferation, which are separable yet coordinately regulated processes, necessitate appropriate production of proteins
We show here that insulin-like growth factor-1 (IGF-1)-induced polymerase I (Pol I) transcription in HEK293 cells is entirely dependent on phosphatidylinositol 3-kinase (PI3K) activity and, is modulated by the mammalian target of rapamycin, which coordinates Pol I transcription with the availability of amino acids
PI3K, mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) Coordinate Growth Factor Signaling to Pol I Transcription with Nutrient Availability—In this study we set out to determine which signaling cascades regulate Pol I transcription in response to the growth factor IGF-1 and amino acid availability in HEK293 cells
Summary
Pol I, RNA polymerase I; DMEM, Dulbecco’s modified Eagle’s medium; PIPES, 1,4-piperazinediethanesulfonic acid; PBS, phosphate-buffered saline; IGF, insulin-like growth factor; HEK, human embryonic kidney; IRS, insulin receptor substrate; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; ChIP, chromatin immunoprecipitation assay. Regulation of Pol I transcription is linked to cellular hypertrophy [9, 10] Despite these findings, little is known of the signaling pathways involved in the control of Pol I transcription. We have investigated the signal transduction pathways that regulate the rRNA gene expression in proliferating mammalian cells (HEK293) in their rapid response to insulin-like growth factor IGF-1 and nutrient availability. We provide evidence for the essential role of PI3K, a modulating role for the mTOR pathways and a minor role for the MAPK cascade, in the regulation of rRNA gene expression by Pol I in response to nutrients and growth factor stimulation. Our results demonstrate that the control of rRNA gene expression can be achieved by modulation of the activity of the Pol I transcription machinery, including an increased promoter occupancy by the essential Pol I transcription factor SL1 following IGF-1 induction
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