Interaction between nuclear insulin receptor substrate-2 and NF-κB in IGF-1 induces response in breast cancer cells.
Despite significant homology between IRS-1 and IRS-2, recent studies have revealed distinct functions for these adaptor proteins in regulating breast cancer progression. Thus far, most of the studies on breast cancer have focused upon IRS-1, the biological pattern of IRS-2 is limited. We demonstrated that depletion of endogenous IRS-2 by antisense strategies impaired cell proliferation after serum withdrawal, blunted PI3K/Akt and NF-κB activation in IGF-1 induced response in MCF-7 and BT-20 breast cancer cells. In addition, IGF-1 promote nuclear translocation of IRS-2 and NF-κB in MCF-7 and BT-20 cells. Nuclear IRS-2 interaction with NF-κB-p65 and PI3K binding tyrosine residues of IRS-2 are crucial for the NF-κB activities. Moreover, nuclear IRS-2 is recruited to the cyclin D1 promoter both in MCF-7 and BT-20 cells. The selective inhibition of NF-κB-65 abolished the occupancy of IRS-2 to the cyclin D1 promoters. Our studies suggest that IRS-2 plays a significant role by activating, at least in part, NF-κB via PI3K/Akt pathway in IGF-1-induced responses in breast cancer cells and the crosstalk between nuclear IRS-2 and NF-κB might be responsible for transcriptional progression of the breast cancer cells.
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710060, PR China. shufangw@hotmail.com
Shufang
S
Wu
Bo
B
Zhou
Lin
L
Xu
Hongzhi
H
Sun
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D055504:Insulin Receptor Substrate Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I