TY - JOUR
T1 - The estrogen receptor α
T2 - insulin receptor substrate 1 complex in breast cancer: Structure-function relationships
AU - Sisci, D.
AU - Morelli, C.
AU - Cascio, S.
AU - Lanzino, M.
AU - Garofalo, C.
AU - Reiss, K.
AU - Garcia, M.
AU - Russo, A.
AU - Andò, S.
AU - Surmacz, E.
PY - 2007/6
Y1 - 2007/6
N2 - Background: Insulin receptor substrate 1 (IRS-1) is a signaling molecule that exerts a key role in mediating cross talk between estrogen receptor α (ERα) and insulin-like growth factor 1 (IGF-1) in breast cancer cells. Previously, we demonstrated that a fraction of IRS-1 binds ERα, translocates to the nucleus, and modulates ERα-dependent transcription at estrogen response elements (ERE). Here, we studied structure-function relationships of the ERα:IRS-1 complex under IGF-1 and/or estradiol (E2) stimulation. Materials and methods: ERα and IRS-1 deletion mutants were used to analyze structural and functional ERα/IRS-1 interactions. IRS-1 binding to ERE and IRS-1 role in ERα-dependent ERE transcription was examined by chromatin immunoprecipitation and gene reporter analysis, respectively. The requirement for IRS-1 in ERα function was tested with RNAi technology. Results: Nuclear translocation of IRS-1 was induced by E2, IGF-1, and a combination of both stimuli. ERα/IRS-1 binding was direct and involved the activation function-1 (AF-1)/DNA binding domain (DBD) region of ERα and two discrete regions of IRS-1 (the N-terminal pleckstrin homology domain and a region within the C-terminus). IRS-1 knock down abrogated IGF-1-dependent transcriptional activity of unliganded ERα, but induced the activity of liganded ERα. Conclusions: ERα/IRS-1 interactions are direct and involve the ERα AF-1/DBD domain and IRS-1 domains mapping within N- and C-terminus. IRS-1 may act as a repressor of liganded ERα and coactivator of unliganded ERα.
AB - Background: Insulin receptor substrate 1 (IRS-1) is a signaling molecule that exerts a key role in mediating cross talk between estrogen receptor α (ERα) and insulin-like growth factor 1 (IGF-1) in breast cancer cells. Previously, we demonstrated that a fraction of IRS-1 binds ERα, translocates to the nucleus, and modulates ERα-dependent transcription at estrogen response elements (ERE). Here, we studied structure-function relationships of the ERα:IRS-1 complex under IGF-1 and/or estradiol (E2) stimulation. Materials and methods: ERα and IRS-1 deletion mutants were used to analyze structural and functional ERα/IRS-1 interactions. IRS-1 binding to ERE and IRS-1 role in ERα-dependent ERE transcription was examined by chromatin immunoprecipitation and gene reporter analysis, respectively. The requirement for IRS-1 in ERα function was tested with RNAi technology. Results: Nuclear translocation of IRS-1 was induced by E2, IGF-1, and a combination of both stimuli. ERα/IRS-1 binding was direct and involved the activation function-1 (AF-1)/DNA binding domain (DBD) region of ERα and two discrete regions of IRS-1 (the N-terminal pleckstrin homology domain and a region within the C-terminus). IRS-1 knock down abrogated IGF-1-dependent transcriptional activity of unliganded ERα, but induced the activity of liganded ERα. Conclusions: ERα/IRS-1 interactions are direct and involve the ERα AF-1/DBD domain and IRS-1 domains mapping within N- and C-terminus. IRS-1 may act as a repressor of liganded ERα and coactivator of unliganded ERα.
KW - Breast cancer
KW - Estrogen receptor alpha (ERa)
KW - Insulin receptor substrate 1 (IRS-1)
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U2 - 10.1093/annonc/mdm232
DO - 10.1093/annonc/mdm232
M3 - Article
C2 - 17591841
AN - SCOPUS:35748930595
SN - 0923-7534
VL - 18
JO - Annals of Oncology
JF - Annals of Oncology
IS - SUPPL. 6
ER -