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PNAS 97 (3): 1032-1037

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

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}UCHSC.edu.

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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   Abstract »    Full Text »    PDF »
The Divergent Orphan Nuclear Receptor ODR-7 Regulates Olfactory Neuron Gene Expression via Multiple Mechanisms in Caenorhabditis elegans.
M. E. Colosimo, S. Tran, and P. Sengupta (2003)
Genetics 165, 1779-1791
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Neonatal Estrogen Down-Regulates Prostatic Androgen Receptor through a Proteosome-Mediated Protein Degradation Pathway.
C. Woodham, L. Birch, and G. S. Prins (2003)
Endocrinology 144, 4841-4850
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Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor {alpha} (ER{alpha}), Differentially Affect ER{alpha} Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells.
V. Marsaud, A. Gougelet, S. Maillard, and J.-M. Renoir (2003)
Mol. Endocrinol. 17, 2013-2027
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The AF-1 and AF-2 Domains of RAR{gamma}2 and RXR{alpha} Cooperate for Triggering the Transactivation and the Degradation of RAR{gamma}2/RXR{alpha} Heterodimers.
M. Gianni, A. Tarrade, E. A. Nigro, E. Garattini, and C. Rochette-Egly (2003)
J. Biol. Chem. 278, 34458-34466
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Extracellular Signal-Regulated Kinase 7, a Regulator of Hormone-Dependent Estrogen Receptor Destruction.
L. M. Henrich, J. A. Smith, D. Kitt, T. M. Errington, B. Nguyen, A. M. Traish, and D. A. Lannigan (2003)
Mol. Cell. Biol. 23, 5979-5988
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Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression.
H. K. Kinyamu and T. K. Archer (2003)
Mol. Cell. Biol. 23, 5867-5881
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The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression.
K. De Bosscher, W. Vanden Berghe, and G. Haegeman (2003)
Endocr. Rev. 24, 488-522
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Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor-{alpha} Protein: Estrogen-Dependent Proteolysis Is Not Essential for Receptor Transactivation Function in the Pituitary.
E. T. Alarid, M. T. Preisler-Mashek, and N. M. Solodin (2003)
Endocrinology 144, 3469-3476
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Specific Ubiquitin-Conjugating Enzymes Promote Degradation of Specific Nuclear Receptor Coactivators.
F. Yan, X. Gao, D. M. Lonard, and Z. Nawaz (2003)
Mol. Endocrinol. 17, 1315-1331
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Mitogen-Activated Protein Kinase Regulates Nuclear Association of Human Progesterone Receptors.
M. Qiu, A. Olsen, E. Faivre, K. B. Horwitz, and C. A. Lange (2003)
Mol. Endocrinol. 17, 628-642
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Sumoylation of the Progesterone Receptor and of the Steroid Receptor Coactivator SRC-1.
A. Chauchereau, L. Amazit, M. Quesne, A. Guiochon-Mantel, and E. Milgrom (2003)
J. Biol. Chem. 278, 12335-12343
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The Aryl Hydrocarbon Receptor Mediates Degradation of Estrogen Receptor {alpha} through Activation of Proteasomes.
M. Wormke, M. Stoner, B. Saville, K. Walker, M. Abdelrahim, R. Burghardt, and S. Safe (2003)
Mol. Cell. Biol. 23, 1843-1855
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The NEDD8 Pathway Is Required for Proteasome-Mediated Degradation of Human Estrogen Receptor (ER)-{alpha} and Essential for the Antiproliferative Activity of ICI 182,780 in ER{alpha}-Positive Breast Cancer Cells.
M. Fan, R. M. Bigsby, and K. P. Nephew (2003)
Mol. Endocrinol. 17, 356-365
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Heregulin Induces Transcriptional Activation of the Progesterone Receptor by a Mechanism That Requires Functional ErbB-2 and Mitogen-Activated Protein Kinase Activation in Breast Cancer Cells.
L. Labriola, M. Salatino, C. J. Proietti, A. Pecci, O. A. Coso, A. R. Kornblihtt, E. H. Charreau, and P. V. Elizalde (2003)
Mol. Cell. Biol. 23, 1095-1111
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Multiple forms of estrogen receptor-alpha in cerebral blood vessels: regulation by estrogen.
C. Stirone, S. P. Duckles, and D. N. Krause (2003)
Am J Physiol Endocrinol Metab 284, E184-E192
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Involvement of Proteasome in the Dynamic Assembly of the Androgen Receptor Transcription Complex.
Z. Kang, A. Pirskanen, O. A. Janne, and J. J. Palvimo (2002)
J. Biol. Chem. 277, 48366-48371
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Progestin and G Protein-Coupled Receptor 30 Inhibit Mitogen-Activated Protein Kinase Activity in MCF-7 Breast Cancer Cells.
T. M. Ahola, N. Alkio, T. Manninen, and T. Ylikomi (2002)
Endocrinology 143, 4620-4626
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Mechanism of Action of Progesterone Antagonists.
S. A. Leonhardt and D. P. Edwards (2002)
Exp Biol Med 227, 969-980
   Abstract »    Full Text »    PDF »
Disruption of Steroid and Prolactin Receptor Patterning in the Mammary Gland Correlates with a Block in Lobuloalveolar Development.
S. L. Grimm, T. N. Seagroves, E. B. Kabotyanski, R. C. Hovey, B. K. Vonderhaar, J. P. Lydon, K. Miyoshi, L. Hennighausen, C. J. Ormandy, A. V. Lee, et al. (2002)
Mol. Endocrinol. 16, 2675-2691
   Abstract »    Full Text »    PDF »

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