Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells.
In breast cancer cells, 17-beta-estradiol (E2) upregulates the expression of insulin receptor substrate 1 (IRS-1), a molecule transmitting insulin-like growth factor-I (IGF-I) signals through the PI-3K/Akt survival pathways. The stimulation of IRS-1 by E2 has been documented on the transcriptional level. Here we studied whether the expression of estrogen receptor ... (ER)-alpha affects IRS molecules post-transcriptionally. We used ER-alpha-negative MDA-MB-231 breast cancer cells and MDA-MB-231 cells with re-expressed ER-alpha. In MDA-MB-231 cells cultured under serum-free conditions, IRS-1 and IRS-2 were degraded through the 26S proteasome and calpain pathways. Re-expression of ER-alpha in MDA-MB-231 cells correlated with enhanced stability of IRS molecules. This effect coincided with significantly reduced ubiquitination of IRS-1 and IRS-2, but did not involve increased IRS-1 and IRS-2 transcription. The interference of ER-alpha with IRS-1 and IRS-2 turnover could rely on the competition for common degradation pathways, as in MDA-MB-231/ER cells, ER-alpha processing was blocked by proteasome and calpain inhibitors. Notably, a fraction of the cytosolic ER-alpha colocalized and coprecipitated with IRS-1 and IRS-2, indicating a possible common destination for these proteins. The stabilization of IRS-1 in MDA-MB-231/ER cells was paralleled by the upregulation of the IRS-1/Akt/GSK-3 pathway and improved survival in the presence of IGF-I, whereas IRS-2 was not involved in IGF-I signaling.
Mesh Terms:
Blotting, Western, Breast Neoplasms, Cell Division, Cell Survival, Cysteine Endopeptidases, Endoplasmic Reticulum, Estrogen Receptor alpha, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Ligands, Microscopy, Confocal, Microscopy, Fluorescence, Multienzyme Complexes, Peptide Hydrolases, Phosphoproteins, Precipitin Tests, Proteasome Endopeptidase Complex, Receptors, Estrogen, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Transcription, Genetic, Tumor Cells, Cultured, Ubiquitin
Blotting, Western, Breast Neoplasms, Cell Division, Cell Survival, Cysteine Endopeptidases, Endoplasmic Reticulum, Estrogen Receptor alpha, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Ligands, Microscopy, Confocal, Microscopy, Fluorescence, Multienzyme Complexes, Peptide Hydrolases, Phosphoproteins, Precipitin Tests, Proteasome Endopeptidase Complex, Receptors, Estrogen, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Transcription, Genetic, Tumor Cells, Cultured, Ubiquitin
Oncogene
Date: Jun. 26, 2003
PubMed ID: 12821935
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