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Submitted on August 7, 2002
Accepted on November 21, 2002
1 Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10Street, Philadelphia, Pennsylvania 19107
* To whom correspondence should be addressed. E-mail: B lupo{at}mail.jci.tju.edu.
The insulin receptor substrate-1 (IRS-1) can translocate to the nuclei and nucleoli of several types of cells. Nuclear translocation can be induced by an activated insulin-like growth factor 1 receptor (IGF-IR), and by certain oncogenes, like the SV40 T antigen and v-src. We have asked whether IRS-2 could also translocate to the nuclei. In addition, we have studied the effects of functional mutations in the IGF-IR on nuclear translocation of IRS proteins. IRS-2 translocates to the nuclei of mouse embryo fibroblasts (MEF) expressing the IGF-IR, but, at variance with IRS-1, does not translocate in cells expressing the SV40 T antigen. Mutations in the tyrosine kinase domain of the IGF-IR abrogate translocation of the IRS proteins. Other mutations in the IGF-IR, that do not interfere with its mitogenicity but inhibit its transforming capacity, result in a decrease in translocation, especially to the nucleoli. Nuclear IRS-1 and IRS-2 interact with the Upstream Binding Factor (UBF), which is a key regulator of RNA polymerase I activity and, therefore, ribosomal RNA synthesis. In 32D cells, wild type, but not mutant IRS-1, causes a significant activation of the rDNA promoter. The interaction of nuclear IRS proteins with UBF1 constitutes the first direct link of these proteins with the rDNA transcription machinery.
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