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The role of insulin receptor substrate‐1 in transformation by v‐src
Author(s) -
Sun Hongzhi,
Baserga Renato
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21352
Subject(s) - proto oncogene tyrosine protein kinase src , irs1 , microbiology and biotechnology , insulin receptor , biology , promoter , receptor , cyclin d1 , insulin receptor substrate , tyrosine kinase , chemistry , insulin , signal transduction , cell cycle , cell , gene , biochemistry , gene expression , endocrinology , insulin resistance
Abstract The insulin receptor substrate‐1 (IRS‐1), a docking protein for both the insulin (InR) and the insulin‐like growth factor‐1 (IGF‐IR) receptors, sends a mitogenic, anti‐differentiation and transforming signal. We now show that down‐regulation of IRS‐1 in cells transformed by v‐src reverses the transformed phenotype (growth in serum‐free medium and colony formation in soft agar). IRS‐1 translocates to nuclei and is found in the cyclin D1 and rDNA promoters. Stat3, which is activated by src, requires both IRS‐1 and src for promoter occupancy. IRS‐1 (by itself or in combination with src) also markedly increases transcription from these two promoters. We also show that IRS‐1 binds to src via its two PI3‐K binding tyrosine residues, and that these two residues are required for transformation of mammary cancer cells expressing v‐src. Taken together, these results indicate a significant role of IRS‐1 in the activation of cell cycle progression genes and transformation of cells by v‐src. J. Cell. Physiol. 215: 725–732, 2008. © 2007 Wiley‐Liss, Inc.