TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL1

Cell. 2004 Dec 29;119(7):969-79. doi: 10.1016/j.cell.2004.11.047.

Abstract

The regulation of ribosome biogenesis in response to environmental conditions is a key aspect of cell growth control. Ribosomal protein (RP) genes are regulated by the nutrient-sensitive, conserved target of rapamycin (TOR) signaling pathway. TOR controls the subcellular localization of protein kinase A (PKA) and the PKA-regulated kinase YAK1. However, the target transcription factor(s) of the TOR-PKA pathway are unknown. We show that regulation of RP gene transcription via TOR and PKA in yeast involves the Forkhead-like transcription factor FHL1 and the two cofactors IFH1 (a coactivator) and CRF1 (a corepressor). TOR, via PKA, negatively regulates YAK1 and maintains CRF1 in the cytoplasm. Upon TOR inactivation, activated YAK1 phosphorylates and activates CRF1. Phosphorylated CRF1 accumulates in the nucleus and competes with IFH1 for binding to FHL1 at RP gene promoters, and thereby inhibits transcription of RP genes. Thus, we describe a signaling mechanism linking an environmental sensor to ribosome biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Motifs
  • Cell Nucleus / metabolism
  • Consensus Sequence
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Fungal*
  • Genes, Fungal / genetics
  • Intracellular Signaling Peptides and Proteins
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Ribosomal Proteins / genetics*
  • Ribosomal Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sirolimus / pharmacology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Two-Hybrid System Techniques

Substances

  • CRF1 protein, S cerevisiae
  • FHL1 protein, S cerevisiae
  • Forkhead Transcription Factors
  • IFH1 protein, S cerevisiae
  • Intracellular Signaling Peptides and Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Repressor Proteins
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins
  • Trans-Activators
  • Transcription Factors
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases
  • YAK1 protein, S cerevisiae
  • Cyclic AMP-Dependent Protein Kinases
  • Proto-Oncogene Proteins p21(ras)
  • Sirolimus