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This version published online on March 19, 2004
Endocrinology, doi:10.1210/en.2003-1470
A more recent version of this article appeared on June 1, 2004
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Submitted on October 31, 2003
Accepted on March 8, 2004

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

Houng-Wei Tsai, John A. Katzenellenbogen, Benita S. Katzenellenbogen, and Margaret A. Shupnik*

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

* To whom correspondence should be addressed. E-mail: mas3x{at}virginia.edu.

17{beta}-Estradiol (E2)-stimulated estrogen receptor (ER){alpha} transcription is accompanied by protein degradation via the 26S-proteasome pathway. Inhibition of proteasome activity stabilizes ER{alpha} protein and abolishes E2-activated transcription, suggesting functional linkages between transcription and degradation. It is not known if ligand-independent ER{alpha} activation is coupled to proteolysis. In pituitary cells, forskolin (FSK) stimulates ER{alpha} 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{alpha} levels. E2 stimulated ERE-mediated transcription 2- to 3-fold and decreased ER{alpha} protein levels to 40%. In contrast, FSK stimulated ER{alpha} transcription without decreasing ER{alpha} protein. Treatment with FSK plus E2 resulted in synergistic ER{alpha} transactivation, and FSK specifically prevented E2-induced ER{alpha} degradation. PKA is required for protection, and was prevented by H89 (a PKA inhibitor) but not PD98059 (a MEK inhibitor). Propyl-pyrazole-triol and R,R-diethyl-tetrahydrochrysene, selective ER{alpha} agonists, reduced ER{alpha} protein by 50% while stimulating ER{alpha} transcriptional activity 4- to 8-fold. The antagonist ICI182,780 similarly decreased ER{alpha} levels but prevented ER activation. FSK prevented all ligand-induced ER{alpha} degradation. Lactacystin, a proteasome inhibitor, abolished E2- but not FSK-stimulated ER{alpha} transcription. Thus, stimulation of ER{alpha} transcription by the PKA-dependent pathway is dissociated from receptor degradation and proteasome activity. These data suggest a mechanism of ER{alpha} transcriptional activation by PKA that is distinct from E2-activation, and that may contribute to the synergistic transcriptional activation of ER{alpha} by ligand-dependent and PKA-dependent pathways.
Key words: Estrogen receptor • Degradation • Protein Kinase A • Estrogen Receptor subtype-selective Ligands




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