title: Nuclear IRS-1 and cancer.
abstract: The family of insulin receptor substrates (IRS) consists of four proteins (IRS-1-IRS-4), which were initially characterized as typical cytosolic adaptor proteins involved in insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) signaling. The first cloned and characterized member of the IRS family, IRS-1, has a predicted molecular weight of 132 kDa, however, as a result of its extensive serine phosphorylation it separates on a SDS gel as a band of approximately 160-185 kDa. In addition to its metabolic and growth-promoting functions, IRS-1 is also suspected to play a role in malignant transformation. The mechanism by which IRS-1 supports tumor growth is not fully understood, and the argument that IRS-1 merely amplifies the signal from the IGF-1R and/or IR requires further investigation. Almost a decade ago, we reported the presence of nuclear IRS-1 in medulloblastoma clinical samples, which express viral oncoprotein, large T-antigen of human polyomavirus JC (JCV T-antigen). This first demonstration of nuclear IRS-1 was confirmed by several other laboratories. Nuclear IRS-1 was also detected by cells expressing the SV40 T-antigen, v-Src, in immortalized fibroblasts stimulated with IGF-I, in hepatocytes, 32D cells, and in an osteosarcoma cell line. More recently, nuclear IRS-1 was detected in breast cancer cells in association with estrogen receptor alpha (ERα), and in JC virus negative medulloblastoma cells expressing estrogen receptor beta (ERβ), further implicating nuclear IRS-1 in cellular transformation. Here, we discuss how nuclear IRS-1 acting on DNA repair fidelity, transcriptional activity, and cell growth can support tumor development and progression.
authors.affiliation: Neurological Cancer Research, Stanley S. Scott Cancer Center, School of Medicine, LSU Health Sciences Center, New Orleans, LA 70112, USA. kreiss@lsuhsc.edu
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Adam
authors.initials: A
authors.lastname: Lassak
authors.forename: Joanna
authors.initials: J
authors.lastname: Trojanek
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I