mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability

Abstract

In cycling cells, transcription of ribosomal RNA genes by RNA polymerase I (Pol I) is tightly coordinated with cell growth. Here, we show that the mammalian target of rapamycin (mTOR) regulates Pol I transcription by modulating the activity of TIF-IA, a regulatory factor that senses nutrient and growth-factor availability. Inhibition of mTOR signaling by rapamycin inactivates TIF-IA and impairs transcription-initiation complex formation. Moreover, rapamycin treatment leads to translocation of TIF-IA into the cytoplasm. Rapamycin-mediated inactivation of TIF-IA is caused by hypophosphorylation of Ser 44 (S44) and hyperphosphorylation of Ser 199 (S199). Phosphorylation at these sites affects TIF-IA activity in opposite ways, for example, phosphorylation of S44 activates and S199 inactivates TIF-IA. The results identify a new target for mTOR-signaling pathways and elucidate the molecular mechanism underlying mTOR-dependent regulation of rRNA synthesis.

Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis

“…In support, previous data have indicated that c-Myc mRNA and protein are readily altered in young humans and animals after muscle contraction or stretch (1,52). Not only can mTOR affect translation initiation and elongation, but it can also influence mRNA expression, particularly genes associated with ribosomal assembly (26,42,50). Using reporter gene activity, Teleman et al (50) found that cMyc, a regulator of ribosome biosynthesis, was a downstream target of mTOR and is upregulated in the presence of insulin and downregulated in response to rapamycin.…”

DNA Binding by the Ribosomal DNA Transcription Factor Rrn3 Is Essential for Ribosomal DNA Transcription

“…), or a substitution mutant (S199D). The substitution of an acidic residue for the serine at 199 has been reported previously to inhibit the ability of Rrn3 to interact with both SL1and RNA polymerase I (43). The data presented in lanes 6 and 7 of Fig.…”

Is Ribosome Synthesis Controlled by Pol I Transcription?

“…[9][10][11], and has been shown to be a prime target for the regulation of the Pol I activity. 8,12,13 To interfere with these mechanisms, we constructed a yeast strain, named CARA (for Constitutive Association of Rrn3 and A43), in which the endogenous, essential Rrn3 factor and the A43 subunit of the Pol I that interacts with Rrn3, 14 were supplied as an Rrn3-A43 fusion protein. 1 The chimeric construct assembled properly within Pol I and formed a constitutively active, non dissociable Pol I-Rrn3 complex.…”