This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shen, T.
Right arrow Articles by Lange, C. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shen, T.
Right arrow Articles by Lange, C. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2001, p. 6122-6131, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6122-6131.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transcriptional Hyperactivity of Human Progesterone Receptors Is Coupled to Their Ligand-Dependent Down-Regulation by Mitogen-Activated Protein Kinase-Dependent Phosphorylation of Serine 294

Tianjie Shen,1 Kathryn B. Horwitz,1 and Carol A. Lange2,*

Department of Medicine, The Molecular Biology Program, and The Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262,1 and Department of Medicine, Department of Pharmacology, and The University of Minnesota Cancer Center, Minneapolis, Minnesota 554552

Received 13 February 2001/Returned for modification 30 March 2001/Accepted 31 May 2001

Breast cancers often exhibit elevated expression of tyrosine kinase growth factor receptors; these pathways influence breast cancer cell growth in part by targeting steroid hormone receptors, including progesterone receptors (PR). To mimic activation of molecules downstream of growth factor-initiated signaling pathways, we overexpressed mitogen-activated protein kinase (MAPK; also known as extracellular signal-regulated kinase) kinase kinase 1 (MEKK1) in T47D human breast cancer cells expressing the B isoform of PR. MEKK1 is a strong activator of p42 and p44 MAPKs. MEKK1 expression increased progestin-mediated transcription 8- to 10-fold above normal PR-driven transcription levels. This was dependent on the presence of a progesterone response element and functional PR. PR protein levels were unchanged by MEKK1 alone but were extensively down-regulated by MEKK1 plus the progestin R5020. MEKK1 expression resulted in phosphorylation of PR on Ser294, a MAPK consensus site known to mediate ligand-dependent PR degradation. MEK inhibitors blocked phosphorylation of Ser294 and attenuated PR transcriptional hyperactivity in response to MEKK1 plus R5020; stabilization of PR by inhibition of the 26S proteasome produced similar results. T47D cells stably expressing mutant S294A PR, in which serine 294 is replaced by alanine, fail to undergo ligand-dependent down-regulation and are resistant to MEKK1-plus-R5020-induced transcriptional synergy but respond to progestins alone. Similarly, c-myc protein levels are synergistically increased by epidermal growth factor and R5020 in cells expressing wild-type PR, but not S294A PR. Thus, highly stable mutant PR are functional in response to progestins but are incapable of cross talk with MAPK-driven pathways. These studies demonstrate a paradoxical coupling between steroid receptor down-regulation and transcriptional hyperactivity. They also suggest a link between phosphorylation of PR by MAPKs in response to peptide growth factor signaling and steroid hormone control of breast cancer cell growth.

* Corresponding author. Mailing address: Department of Medicine, Department of Pharmacology, and The University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware St. SE, Minneapolis MN 55455. Phone: (612) 626-0621. Fax: (612) 624-3913. E-mail: Lange047{at}tc.umn.edu.

Molecular and Cellular Biology, September 2001, p. 6122-6131, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6122-6131.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Daniel, A. R., Lange, C. A. (2009). Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells. Proc. Natl. Acad. Sci. USA 106: 14287-14292 [Abstract] [Full Text]  
  • Jacobsen, B. M., Jambal, P., Schittone, S. A., Horwitz, K. B. (2009). ALU Repeats in Promoters Are Position-Dependent Co-Response Elements (coRE) that Enhance or Repress Transcription by Dimeric and Monomeric Progesterone Receptors. Mol. Endocrinol. 23: 989-1000 [Abstract] [Full Text]  
  • Dressing, G. E, Hagan, C. R, Knutson, T. P, Daniel, A. R, Lange, C. A (2009). Progesterone receptors act as sensors for mitogenic protein kinases in breast cancer models. Endocr Relat Cancer 16: 351-361 [Abstract] [Full Text]  
  • Proietti, C. J., Rosemblit, C., Beguelin, W., Rivas, M. A., Diaz Flaque, M. C., Charreau, E. H., Schillaci, R., Elizalde, P. V. (2009). Activation of Stat3 by Heregulin/ErbB-2 through the Co-Option of Progesterone Receptor Signaling Drives Breast Cancer Growth. Mol. Cell. Biol. 29: 1249-1265 [Abstract] [Full Text]  
  • Gopinathan, L., Hannon, D. B., Peters, J. M., Vanden Heuvel, J. P. (2009). Regulation of Peroxisome Proliferator-Activated Receptor-{alpha} by MDM2. Toxicol Sci 108: 48-58 [Abstract] [Full Text]  
  • Faivre, E. J., Daniel, A. R., Hillard, C. J., Lange, C. A. (2008). Progesterone Receptor Rapid Signaling Mediates Serine 345 Phosphorylation and Tethering to Specificity Protein 1 Transcription Factors. Mol. Endocrinol. 22: 823-837 [Abstract] [Full Text]  
  • Arpino, G., Wiechmann, L., Osborne, C. K., Schiff, R. (2008). Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance. Endocr. Rev. 29: 217-233 [Abstract] [Full Text]  
  • Forster, C., Burek, M., Romero, I. A., Weksler, B., Couraud, P.-O., Drenckhahn, D. (2008). Differential effects of hydrocortisone and TNF{alpha} on tight junction proteins in an in vitro model of the human blood-brain barrier. J. Physiol. 586: 1937-1949 [Abstract] [Full Text]  
  • Lewis, A. E., Rusten, M., Hoivik, E. A., Vikse, E. L., Hansson, M. L., Wallberg, A. E., Bakke, M. (2008). Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7. Mol. Endocrinol. 22: 91-104 [Abstract] [Full Text]  
  • Daniel, A. R., Faivre, E. J., Lange, C. A. (2007). Phosphorylation-Dependent Antagonism of Sumoylation Derepresses Progesterone Receptor Action in Breast Cancer Cells. Mol. Endocrinol. 21: 2890-2906 [Abstract] [Full Text]  
  • Weigel, N. L., Moore, N. L. (2007). Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions. Mol. Endocrinol. 21: 2311-2319 [Abstract] [Full Text]  
  • Carnevale, R. P., Proietti, C. J., Salatino, M., Urtreger, A., Peluffo, G., Edwards, D. P., Boonyaratanakornkit, V., Charreau, E. H., de Kier Joffe, E. B., Schillaci, R., Elizalde, P. V. (2007). Progestin Effects on Breast Cancer Cell Proliferation, Proteases Activation, and in Vivo Development of Metastatic Phenotype All Depend on Progesterone Receptor Capacity to Activate Cytoplasmic Signaling Pathways. Mol. Endocrinol. 21: 1335-1358 [Abstract] [Full Text]  
  • Romano, A., Delvoux, B., Fischer, D.-C., Groothuis, P. (2007). The PROGINS polymorphism of the human progesterone receptor diminishes the response to progesterone. J Mol Endocrinol 38: 331-350 [Abstract] [Full Text]  
  • Faivre, E. J., Lange, C. A. (2007). Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells. Mol. Cell. Biol. 27: 466-480 [Abstract] [Full Text]  
  • Liu, B., Wu, J.-f., Zhan, Y.-y., Chen, H.-z., Zhang, X.-y., Wu, Q. (2007). Regulation of the Orphan Receptor TR3 Nuclear Functions by c-Jun N Terminal Kinase Phosphorylation. Endocrinology 148: 34-44 [Abstract] [Full Text]  
  • Tung, L., Abdel-Hafiz, H., Shen, T., Harvell, D. M. E., Nitao, L. K., Richer, J. K., Sartorius, C. A., Takimoto, G. S., Horwitz, K. B. (2006). Progesterone Receptors (PR)-B and -A Regulate Transcription by Different Mechanisms: AF-3 Exerts Regulatory Control over Coactivator Binding to PR-B. Mol. Endocrinol. 20: 2656-2670 [Abstract] [Full Text]  
  • Volakakis, N., Malewicz, M., Kadkhodai, B., Perlmann, T., Benoit, G. (2006). Characterization of the Nurr1 ligand-binding domain co-activator interaction surface.. J Mol Endocrinol 37: 317-326 [Abstract] [Full Text]  
  • Alarid, E. T. (2006). Lives and Times of Nuclear Receptors. Mol. Endocrinol. 20: 1972-1981 [Abstract] [Full Text]  
  • Henley, D. V., Korach, K. S. (2006). Endocrine-Disrupting Chemicals Use Distinct Mechanisms of Action to Modulate Endocrine System Function. Endocrinology 147: s25-s32 [Abstract] [Full Text]  
  • Forster, C., Waschke, J., Burek, M., Leers, J., Drenckhahn, D. (2006). Glucocorticoid effects on mouse microvascular endothelial barrier permeability are brain specific. J. Physiol. 573: 413-425 [Abstract] [Full Text]  
  • Han, S. J., DeMayo, F. J., Xu, J., Tsai, S. Y., Tsai, M.-J., O'Malley, B. W. (2006). Steroid Receptor Coactivator (SRC)-1 and SRC-3 Differentially Modulate Tissue-Specific Activation Functions of the Progesterone Receptor. Mol. Endocrinol. 20: 45-55 [Abstract] [Full Text]  
  • Rochette-Egly, C. (2005). Dynamic Combinatorial Networks in Nuclear Receptor-mediated Transcription. J. Biol. Chem. 280: 32565-32568 [Full Text]  
  • Watanabe, H., Nonoguchi, K., Sakurai, T., Masuda, T., Itoh, K., Fujita, J. (2005). A novel protein Depp, which is induced by progesterone in human endometrial stromal cells activates Elk-1 transcription factor. Mol Hum Reprod 11: 471-476 [Abstract] [Full Text]  
  • Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A. R., Molinolo, A. A., Frahm, I., Charreau, E. H., Schillaci, R., Elizalde, P. V. (2005). Progestins Induce Transcriptional Activation of Signal Transducer and Activator of Transcription 3 (Stat3) via a Jak- and Src-Dependent Mechanism in Breast Cancer Cells. Mol. Cell. Biol. 25: 4826-4840 [Abstract] [Full Text]  
  • Smid-Koopman, E., Kuhne, L. C. M., Hanekamp, E. E., Gielen, S. C.J.P., De Ruiter, P. E., Grootegoed, J. A., Helmerhorst, T. J.M., Burger, C. W., Brinkmann, A. O., Huikeshoven, F. J., Blok, L. J. (2005). Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines. Reproductive Sciences 12: 285-292 [Abstract]  
  • Narayanan, R., Edwards, D. P., Weigel, N. L. (2005). Human Progesterone Receptor Displays Cell Cycle-Dependent Changes in Transcriptional Activity. Mol. Cell. Biol. 25: 2885-2898 [Abstract] [Full Text]  
  • Kinyamu, H K, Chen, J, Archer, T K (2005). Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J Mol Endocrinol 34: 281-297 [Abstract] [Full Text]  
  • Skildum, A., Faivre, E., Lange, C. A. (2005). Progesterone Receptors Induce Cell Cycle Progression via Activation of Mitogen-Activated Protein Kinases. Mol. Endocrinol. 19: 327-339 [Abstract] [Full Text]  
  • Pierson-Mullany, L. K., Lange, C. A. (2004). Phosphorylation of Progesterone Receptor Serine 400 Mediates Ligand-Independent Transcriptional Activity in Response to Activation of Cyclin-Dependent Protein Kinase 2. Mol. Cell. Biol. 24: 10542-10557 [Abstract] [Full Text]  
  • Gonzalez-Flores, O., Shu, J., Camacho-Arroyo, I., Etgen, A. M. (2004). Regulation of Lordosis by Cyclic 3',5'-Guanosine Monophosphate, Progesterone, and Its 5{alpha}-Reduced Metabolites Involves Mitogen-Activated Protein Kinase. Endocrinology 145: 5560-5567 [Abstract] [Full Text]  
  • Tsai, H.-W., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Shupnik, M. A. (2004). Protein Kinase A Activation of Estrogen Receptor {alpha} Transcription Does Not Require Proteasome Activity and Protects the Receptor from Ligand-Mediated Degradation. Endocrinology 145: 2730-2738 [Abstract] [Full Text]  
  • Jansen, M. S., Nagel, S. C., Miranda, P. J., Lobenhofer, E. K., Afshari, C. A., McDonnell, D. P. (2004). Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc. Natl. Acad. Sci. USA 101: 7199-7204 [Abstract] [Full Text]  
  • Lange, C. A. (2004). Making Sense of Cross-Talk between Steroid Hormone Receptors and Intracellular Signaling Pathways: Who Will Have the Last Word?. Mol. Endocrinol. 18: 269-278 [Abstract] [Full Text]  
  • Kolluri, S. K., Bruey-Sedano, N., Cao, X., Lin, B., Lin, F., Han, Y.-H., Dawson, M. I., Zhang, X.-k. (2003). Mitogenic Effect of Orphan Receptor TR3 and Its Regulation by MEKK1 in Lung Cancer Cells. Mol. Cell. Biol. 23: 8651-8667 [Abstract] [Full Text]  
  • De Bosscher, K., Vanden Berghe, W., Haegeman, G. (2003). The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression. Endocr. Rev. 24: 488-522 [Abstract] [Full Text]  
  • Alarid, E. T., Preisler-Mashek, M. T., Solodin, N. M. (2003). 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. Endocrinology 144: 3469-3476 [Abstract] [Full Text]  
  • Cui, X., Zhang, P., Deng, W., Oesterreich, S., Lu, Y., Mills, G. B., Lee, A. V. (2003). Insulin-Like Growth Factor-I Inhibits Progesterone Receptor Expression in Breast Cancer Cells via the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway: Progesterone Receptor as a Potential Indicator of Growth Factor Activity in Breast Cancer. Mol. Endocrinol. 17: 575-588 [Abstract] [Full Text]  
  • Qiu, M., Olsen, A., Faivre, E., Horwitz, K. B., Lange, C. A. (2003). Mitogen-Activated Protein Kinase Regulates Nuclear Association of Human Progesterone Receptors. Mol. Endocrinol. 17: 628-642 [Abstract] [Full Text]  
  • Labriola, L., Salatino, M., Proietti, C. J., Pecci, A., Coso, O. A., Kornblihtt, A. R., Charreau, E. H., Elizalde, P. V. (2003). 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. Mol. Cell. Biol. 23: 1095-1111 [Abstract] [Full Text]  
  • Ahola, T. M., Alkio, N., Manninen, T., Ylikomi, T. (2002). Progestin and G Protein-Coupled Receptor 30 Inhibit Mitogen-Activated Protein Kinase Activity in MCF-7 Breast Cancer Cells. Endocrinology 143: 4620-4626 [Abstract] [Full Text]  
  • Qi, X., Pramanik, R., Wang, J., Schultz, R. M., Maitra, R. K., Han, J., DeLuca, H. F., Chen, G. (2002). The p38 and JNK Pathways Cooperate to trans-Activate Vitamin D Receptor via c-Jun/AP-1 and Sensitize Human Breast Cancer Cells to Vitamin D3-induced Growth Inhibition. J. Biol. Chem. 277: 25884-25892 [Abstract] [Full Text]  
  • Richer, J. K., Jacobsen, B. M., Manning, N. G., Abel, M. G., Wolf, D. M., Horwitz, K. B. (2002). Differential Gene Regulation by the Two Progesterone Receptor Isoforms in Human Breast Cancer Cells. J. Biol. Chem. 277: 5209-5218 [Abstract] [Full Text]  
  • Floyd, Z. E., Stephens, J. M. (2002). Interferon-gamma -mediated Activation and Ubiquitin-Proteasome-dependent Degradation of PPARgamma in Adipocytes. J. Biol. Chem. 277: 4062-4068 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»