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PNAS 97 (3): 1032-1037

Copyright © 2000 by the National Academy of Sciences.


Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome

Carol A. Lange*, Tianjie Shen, and Kathryn B. Horwitz{dagger}

Department of Medicine, The Molecular Biology Program, and The Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262

Received for publication September 1, 1999.

Abstract: Ligand-dependent down-regulation that leads to rapid and extensive loss of protein is characteristic of several nuclear steroid receptors, including human progesterone receptors (PRs). In breast cancer cells, >95% of PRs are degraded 6 h after the start of progestin treatment. The mechanism for down-regulation is unknown. We examined the role of PR phosphorylation by mitogen-activated protein kinases (MAPKs) in this process. Lactacystin and calpain inhibitor I, specific inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and ubiquitinated conjugates of PR accumulated in cells. Ligand-dependent PR degradation was also blocked by specific inhibition of p42 and p44 MAPKs. To define the targets of phosphorylation by this kinase, two serine/proline MAPK consensus sites on PR were mutated. We demonstrate that mutation of PR serine-294 to alanine (S294A) specifically and completely prevents ligand-dependent receptor down-regulation. We also find that rapid, ligand-independent degradation of immature PR intermediates occurs by a proteasome-mediated pathway. These results demonstrate that PR destruction, by either of two alternate routes, is mediated by the 26S proteasome. Specifically, down-regulation of mature PRs occurs by a mechanism in which ligand binding activates PR phosphorylation by MAPKs at a unique serine residue, which then targets the receptors for degradation.

* Present address: University of Minnesota Cancer Center and Department of Medicine, University of Minnesota, Minneapolis, MN 55455.

{dagger} To whom reprint requests should be addressed. E-mail: kate.horwitz{at}

Edited by Ronald M. Evans, The Salk Institute for Biological Studies, San Diego, CA, and approved November 30, 1999

This paper was submitted directly (Track II) to the PNAS office.

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Dimerization with Retinoid X Receptors and Phosphorylation Modulate the Retinoic Acid-induced Degradation of Retinoic Acid Receptors {alpha} and {gamma} through the Ubiquitin-Proteasome Pathway.
E. Kopf, J.-L. Plassat, V. Vivat, H. de The, P. Chambon, and C. Rochette-Egly (2000)
J. Biol. Chem. 275, 33280-33288
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MAP Kinases and the Regulation of Nuclear Receptors.
J. M. Kyriakis (2000)
Sci. STKE 2000, pe1
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Dimerization with RXRs and phosphorylation modulate the retinoic acid-induced degradation of RAR{alpha} and RAR{gamma} and through the ubiquitin-proteasome pathway.
E. Kopf, J.-L. Plassat, V. Vivat, H. de The, P. Chambon, and C. Rochette-Egly (2000)
J. Biol. Chem.
   Abstract »
The Classical Progesterone Receptor Associates with p42 MAPK and Is Involved in Phosphatidylinositol 3-Kinase Signaling in Xenopus Oocytes.
C. P. Bagowski, J. W. Myers, and J. E. Ferrell Jr. (2001)
J. Biol. Chem. 276, 37708-37714
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The Development-associated Cleavage of Lens Connexin 45.6 by Caspase-3-like Protease Is Regulated by Casein Kinase II-mediated Phosphorylation.
X. Yin, S. Gu, and J. X. Jiang (2001)
J. Biol. Chem. 276, 34567-34572
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Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-alpha.
M. T. Preisler-Mashek, N. Solodin, B. L. Stark, M. K. Tyriver, and E. T. Alarid (2002)
Am J Physiol Endocrinol Metab 282, E891-E898
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