Dual regulation of upstream binding factor 1 levels by IRS-1 and ERKs in IGF-1-receptor signaling

J Cell Physiol. 2007 Sep;212(3):780-6. doi: 10.1002/jcp.21072.

Abstract

The Upstream Binding Factor 1 (UBF1) is a nucleolar protein that participates in the regulation of RNA polymerase I activity and ribosomal RNA (rRNA) synthesis. In 32D myeloid cells expressing the type 1 insulin-like growth factor receptor (IGF-IR), the UBF1 protein (but not its mRNA) is down regulated when the cells are shifted from Interleukin-3 (IL-3) to IGF-1. Ectopic expression of insulin receptor substrate-1 (IRS-1) in these cells inhibits the down-regulation of UBF1. We now show that the stability of UBF1 in 32D-derived cells requires also a signal from the extracellular regulated kinases (ERKs). When ERKs signaling is defective, as in cells over-expressing the insulin receptor (InR) or selected mutants of the IGF-1R, UBF1 is down-regulated, even in the presence of IRS-1. The down-regulation is corrected by the expression of an activated Ha-ras, which stimulates ERKs activity. Mutations at threonines 117 and 201 of UBF1, known to be phosphorylated by ERKs, cause its down-regulation. However, when IRS-2, instead of IRS-1, is ectopically expressed in 32D InR cells, ERKs phosphorylation is increased and UBF is stabilized. Taken together, these results indicate that in 32D-derived myeloid cells expressing either the IGF-IR or the InR, UBF1 levels are regulated by signaling from both IRS proteins and ERKs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Cell Line
  • Down-Regulation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-3 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mutation
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism*
  • Nitriles / pharmacology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Pol1 Transcription Initiation Complex Proteins / genetics
  • Pol1 Transcription Initiation Complex Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, Insulin / metabolism
  • Signal Transduction* / drug effects
  • Time Factors
  • Transfection

Substances

  • Butadienes
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Interleukin-3
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Nitriles
  • Phosphoproteins
  • Pol1 Transcription Initiation Complex Proteins
  • Protein Kinase Inhibitors
  • U 0126
  • transcription factor UBF
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Extracellular Signal-Regulated MAP Kinases
  • Proto-Oncogene Proteins p21(ras)