Dual regulation of upstream binding factor 1 levels by IRS-1 and ERKs in IGF-1-receptor signaling.
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.
Sun
Hongzhi
H
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Tu
Xiao
X
Liu
Mingli
M
Baserga
Renato
R
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
D002070:Butadienes; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009570:Nitriles; D010750:Phosphoproteins; D035463:Pol1 Transcription Initiation Complex Proteins; D047428:Protein Kinase Inhibitors; C113580:U 0126; C063844:transcription factor UBF; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)