The Journal of biological chemistry, 2001-03, Vol.276 (13), p.9817-9824
2001
Details
- Autor(en) / Beteiligte
- Titel
- Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance
- Ist Teil von
- The Journal of biological chemistry, 2001-03, Vol.276 (13), p.9817-9824
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2001
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERalpha. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERalpha in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9258eISSN: 1083-351XDOI: 10.1074/jbc.M010840200Titel-ID: cdi_proquest_miscellaneous_17832292
- Format
- –
- Schlagworte
- AKT protein, Animals, Antineoplastic Agents, Hormonal - pharmacology, Apoptosis, ApS2 gene, Bcl-2 protein, Blotting, Western, Breast Neoplasms - drug therapy, Breast Neoplasms - metabolism, Breast Neoplasms - pathology, Cell Division - drug effects, Cell Survival, Chloramphenicol O-Acetyltransferase - metabolism, Chromones - pharmacology, COS Cells, Cytokines - metabolism, Drug Resistance, Neoplasm, Enzyme Activation, Enzyme Inhibitors - pharmacology, Estrogen Antagonists - pharmacology, Estrogen Receptor alpha, Estrogen Receptor Modulators - pharmacology, Estrogens - metabolism, Growth Differentiation Factor 15, Humans, macrophage inhibitory cytokine 1, Models, Biological, Morpholines - pharmacology, Phosphates - metabolism, Phosphatidylinositol 3-Kinases - metabolism, Phosphoric Monoester Hydrolases - pharmacology, Phosphorylation, Plasmids - metabolism, Precipitin Tests, Protein-Serine-Threonine Kinases, Proteins - metabolism, Proto-Oncogene Proteins - metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2 - metabolism, PTEN Phosphohydrolase, Receptors, Estrogen - metabolism, Serine - metabolism, Signal Transduction, Tamoxifen - pharmacology, Time Factors, Transfection, Trefoil Factor-1, Tumor Cells, Cultured, Tumor Suppressor Proteins, Up-Regulation