Nuclear translocation of insulin receptor substrate-1 by oncogenes and Igf-I. Effect on ribosomal RNA synthesis.
The insulin receptor substrate-1 (IRS-1) is one of the major substrates of both the insulin and IGF-I receptors and is generally localized in the cytosol/membrane fraction of the cell. We show here that a substantial fraction of IRS-1 is translocated to the nucleus in mouse embryo fibroblasts (MEF) expressing the simian virus 40 T antigen. Nuclear translocation of IRS-1 occurs also in MEF stimulated with IGF-I or in MEF expressing the oncogene v-src. Nuclear translocation of IRS-1 can be demonstrated by confocal microscopy, immunohistochemistry, or subcellular fractionation. An antibody to IRS-1 immunoprecipitates from nuclear fractions (but not from cytosolic fractions) the upstream binding factor, which is a key regulator of RNA polymerase I activity and ribosomal RNA (rRNA) synthesis. In agreement with this finding, in 32D murine hemopoietic cells, nuclear translocation of IRS-1 correlates with a markedly increased rRNA synthesis. Our experiments suggest that nuclear IRS-1 may play a specialized role in rRNA synthesis and/or processing.
Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, 624 BLSB, Philadelphia, Pennsylvania 19107, USA.
Xiao
X
Tu
Priti
P
Batta
Nathalie
N
Innocent
Marco
M
Prisco
Ivan
I
Casaburi
Barbara
B
Belletti
Renato
R
Baserga
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D015153:Blotting, Western; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D020123:Sirolimus / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors
D000952:Antigens, Polyomavirus Transforming; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D019384:Nucleic Acid Synthesis Inhibitors; D010750:Phosphoproteins; D012335:RNA, Ribosomal; D003609:Dactinomycin; D007334:Insulin-Like Growth Factor I; D020123:Sirolimus