scholarly journals Nuclear Translocation of Insulin Receptor Substrate-1 by the Simian Virus 40 T Antigen and the Activated Type 1 Insulin-like Growth Factor Receptor

2002 ◽  
Vol 277 (35) ◽  
pp. 32078-32085 ◽  
Author(s):  
Marco Prisco ◽  
Francesca Santini ◽  
Raffaele Baffa ◽  
Mingli Liu ◽  
Robert Drakas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Type 1 Insulin-Like Growth Factor Receptor/Insulin Receptor Substrate 1 Signaling Confers Pathogenic Activity on Breast Tumor Cells Lacking REST

2015 ◽  
Vol 35 (17) ◽  
pp. 2991-3004 ◽  
Author(s):  
Kassondra Meyer ◽  
Brittany Albaugh ◽  
Barry Schoenike ◽  
Avtar Roopra
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Growth Factor Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Like Growth Factor ◽  
Insulin Receptor Substrate 1 ◽  
Breast Tumor Cells

Loss of repressor element 1 silencing transcription factor (REST) occurs in 20% of breast cancers and correlates with a poor patient prognosis. However, the molecular basis for enhanced malignancy in tumors lacking REST (RESTless) is only partially understood. We used multiplatform array data from the Cancer Genome Atlas to identify consistent changes in key signaling pathways. Of the proteins screened in the reverse-phase protein array, we found that insulin receptor substrate 1 (IRS1) is the most highly upregulated protein in RESTless breast tumors. Analysis of breast tumor cell lines showed that REST directly represses IRS1, and cells lacking REST have increased levels of IRS1 mRNA and protein. We find that the upregulation of IRS1 function is both necessary and sufficient for enhanced signaling and growth in breast cancer cells lacking REST. IRS1 overexpression is sufficient to phenocopy the enhanced activation of the signaling hubs AKT and mitogen-activated protein kinase (MAPK) of MCF7 cells lacking REST. Loss of REST renders MCF7 and MDA-MB-231 breast tumor cells dependent on IRS1 activity for colony formation in soft agar. Inhibition of the type 1 insulin-like growth factor receptor (IGF1R) reduces the enhanced signaling, growth, and migration in breast tumor cells that occur upon REST loss. We show that loss of REST induces a pathogenic program that works through the IGF1R/IRS1 pathway.

scholarly journals Association of insulin receptor substrate 1 with simian virus 40 large T antigen.

1995 ◽  
Vol 15 (8) ◽  
pp. 4232-4239 ◽  
Author(s):  
Z L Fei ◽  
C D'Ambrosio ◽  
S Li ◽  
E Surmacz ◽  
R Baserga
Keyword(s):  
Insulin Receptor ◽  
Mouse Embryo ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Insulin Receptor Substrate ◽  
Large T Antigen ◽  
Sv40 T Antigen ◽  
Insulin Receptor Substrate 1 ◽  
Embryo Cells

Mouse embryo cells expressing a wild-type number of insulin-like growth factor I receptors (IGF-IR) (W cells) can be transformed either by simian virus 40 large T antigen (SV40 T) or by overexpressed insulin receptor substrate 1 (IRS-1), singly transfected. Neither SV40 T antigen nor IRS-1, individually, can transform mouse embryo cells with a targeted disruption of the IGF-IR genes (R- cells). However, cotransfection of SV40 T antigen and IRS-1 does transform R- cells. In this study, using different antibodies and different cell lines, we found that SV40 T antigen and IRS-1 are coprecipitated from cell lysates in a specific fashion, regardless of whether the lysates are immunoprecipitated with an antibody to SV40 T antigen or an antibody to IRS-1. The same antibody to SV40 T antigen, however, fails to coprecipitate another substrate of IGF-IR, the transforming protein Shc, and two other signal-transducing molecules, Grb2 and Sos. Finally, an SV40 T antigen lacking the amino-terminal 250 amino acids fails to coprecipitate IRS-1 and also fails to transform R- cells overexpressing mouse IRS-1. These experiments indicate that IRS-1 associates with SV40 T antigen and that this association plays a critical role in the combined ability of these proteins to transform R- cells. This finding is discussed in light of the crucial role of the IGF-IR in the establishment and maintenance of the transformed phenotype.

scholarly journals Interaction between Simian Virus 40 Large T Antigen and Insulin Receptor Substrate 1 Is Disrupted by the K1 Mutation, Resulting in the Loss of Large T Antigen-Mediated Phosphorylation of Akt

2008 ◽  
Vol 82 (9) ◽  
pp. 4521-4526 ◽  
Author(s):  
Yongjun Yu ◽  
James C. Alwine
Keyword(s):  
Insulin Receptor ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Akt Signaling ◽  
T Antigen ◽  
Binding Motif ◽  
Insulin Receptor Substrate ◽  
Large T Antigen ◽  
Insulin Receptor Substrate 1 ◽  
Akt Phosphorylation

ABSTRACT The cellular kinase Akt is a key controller of cellular metabolism, growth, and proliferation. Many viruses activate Akt due to its beneficial effects on viral replication. We previously showed that wild-type (WT) simian virus 40 (SV40) large T antigen (TAg) inhibits apoptosis via the activation of PI3K/Akt signaling. Here we show that WT TAg expressed from recombinant adenoviruses in U2OS cells induced the phosphorylation of Akt at both T308 and S473. In contrast, Akt phosphorylation was eliminated by the K1 mutation (E107K) within the retinoblastoma protein (Rb) binding motif of TAg. This suggested that Akt phosphorylation may depend on TAg binding to Rb or one of its family members. However, in Rb-negative SAOS2 cells depleted of p107 and p130 by using small hairpin RNAs (shRNAs), WT TAg still mediated Akt phosphorylation. These results suggested that the K1 mutation affects another TAg function. WT-TAg-mediated phosphorylation of Akt was inhibited by a PI3K inhibitor, suggesting that the effects of TAg originated upstream of PI3K; thus, we examined the requirement for insulin receptor substrate 1 (IRS1), which binds and activates PI3K. Depletion of IRS1 by shRNAs abolished the WT-TAg-mediated phosphorylation of Akt. Immunoprecipitation studies showed that the known interaction between TAg and IRS1 is significantly weakened by the K1 mutation. These data indicate that the K1 mutation disrupts not only Rb binding but also IRS1 binding, contributing to the loss of activation of PI3K/Akt signaling.

Insulin-Like Growth Factor I Receptor Signaling and Nuclear Translocation of Insulin Receptor Substrates 1 and 2

2003 ◽  
Vol 17 (3) ◽  
pp. 472-486 ◽  
Author(s):  
HongZhi Sun ◽  
Xiao Tu ◽  
Marco Prisco ◽  
An Wu ◽  
Ivan Casiburi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Ribosomal Dna ◽  
Nuclear Translocation ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Binding Factor ◽  
Irs Proteins ◽  
Upstream Binding Factor

Abstract 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, such as the Simian virus 40 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 expressing the IGF-IR, but, at variance with IRS-1, does not translocate in cells expressing the Simian virus 40 T antigen. Mutations in the tyrosine kinase domain of the IGF-IR abrogate translocation of the IRS proteins. Other mutations in the IGF-IR, which 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, which is a key regulator of RNA polymerase I activity and, therefore, rRNA synthesis. In 32D cells, wild-type, but not mutant, IRS-1 causes a significant activation of the ribosomal DNA promoter. The interaction of nuclear IRS proteins with upstream binding factor 1 constitutes the first direct link of these proteins with the ribosomal DNA transcription machinery.

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