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Protein Kinase A Activation of Estrogen Receptor Transcription Does Not Require Proteasome Activity and Protects the Receptor from Ligand-Mediated Degradation

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia (H.-W.T., M.A.S.), Charlottesville, Virginia 22908; and Departments of Chemistry (J.A.K.) and Molecular and Integrative Physiology (B.S.K.), University of Illinois, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Dr. Margaret A. Shupnik, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Box 800578, Charlottesville, Virginia 22908. E-mail: mas3x{at}virginia.edu.

17ß-Estradiol (E2)-stimulated estrogen receptor (ER) transcription is accompanied by protein degradation via the 26S-proteasome pathway. Inhibition of proteasome activity stabilizes ER protein and abolishes E2-activated transcription, suggesting functional linkages between transcription and degradation. It is not known whether ligand-independent ER activation is coupled to proteolysis. In pituitary cells, forskolin (FSK) stimulates ER transcription through the protein kinase A (PKA) pathway. This study examined interactions between E2-dependent and PKA-stimulated pathways in GH₃ cells by measuring transcription of a transfected reporter gene and endogenous ER levels. E2 stimulated estrogen response element-mediated transcription 2- to 3-fold and decreased ER protein levels to 40%. In contrast, FSK stimulated ER transcription without decreasing ER protein. Treatment with FSK plus E2 resulted in synergistic ER transactivation, and FSK specifically prevented E2-induced ER degradation. PKA is required for protection and was prevented by H89 (a PKA inhibitor), but not PD98059 (a MAPK kinase inhibitor). Propyl-pyrazole-triol and R,R-diethyl-tetrahydrochrysene, selective ER agonists, reduced ER protein by 50% while stimulating ER transcriptional activity 4- to 8-fold. The antagonist ICI 182,780 similarly decreased ER levels, but prevented ER activation. FSK prevented all ligand-induced ER degradation. Lactacystin, a proteasome inhibitor, abolished E2-stimulated, but not FSK-stimulated, ER transcription. Thus, stimulation of ER transcription by the PKA-dependent pathway is dissociated from receptor degradation and proteasome activity. These data suggest a mechanism of ER transcriptional activation by PKA that is distinct from E2 activation and that may contribute to the synergistic transcriptional activation of ER by ligand-dependent and PKA-dependent pathways.

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