Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Mol. Cell. Biol. 20 (17): 6612-6625

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, September 2000, p. 6612-6625, Vol. 20, No. 17
Copyright © 2000, American Society for Microbiology. All rights reserved.

The SMRT Corepressor Is Regulated by a MEK-1 Kinase Pathway: Inhibition of Corepressor Function Is Associated with SMRT Phosphorylation and Nuclear Export

Suk-Hyun Hong and Martin L. Privalsky*

Section of Microbiology, University of California at Davis, Davis, California 95616

Received 13 December 1999/Returned for modification 29 February 2000/Accepted 24 May 2000

The SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor participates in the repression of target gene expression by a variety of transcription factors, including the nuclear hormone receptors, promyelocytic leukemia zinc finger protein, and B-cell leukemia protein 6. The ability of SMRT to associate with these transcription factors and thereby to mediate repression is strongly inhibited by activation of tyrosine kinase signaling pathways, such as that represented by the epidermal growth factor receptor. We report here that SMRT function is potently inhibited by a mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) cascade that operates downstream of this growth factor receptor. Intriguingly, the SMRT protein is a substrate for phosphorylation by protein kinases operating at multiple levels in this MAPKKK pathway, including the MAPKs, MAPK-extracellular signal-regulated kinase 1 (MEK-1), and MEK-1 kinase (MEKK-1). Phosphorylation of SMRT by MEKK-1 and, to a lesser extent, MEK-1 inhibits the ability of SMRT to physically tether to its transcription factor partners. Notably, activation of MEKK-1 or MEK-1 signaling in transfected cells also leads to a redistribution of the SMRT protein from a nuclear compartment to a more perinuclear or cytoplasmic compartment. We suggest that SMRT-mediated repression is regulated by the MAPKKK cascade and that changes both in the affinity of SMRT for its transcription factors and in the subcellular distribution of SMRT contribute to the loss of SMRT function that is observed in response to kinase signal transduction.

* Corresponding author. Mailing address: Section of Microbiology, University of California at Davis, One Shields Ave., Davis, CA 95616. Phone: (530) 752-3013. Fax: (530) 752-9014. E-mail: mlprivalsky{at}

Molecular and Cellular Biology, September 2000, p. 6612-6625, Vol. 20, No. 17
Copyright © 2000, American Society for Microbiology. All rights reserved.

Rescue of a primary myelofibrosis model by retinoid-antagonist therapy.
S.-H. Hong, M. Dvorak-Ewell, H. Y. Stevens, G. D. Barish, G. L. Castro, R. Nofsinger, J. A. Frangos, D. Shoback, and R. M. Evans (2013)
PNAS 110, 18820-18825
   Abstract »    Full Text »    PDF »
Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications.
F. Montemurro, S. Di Cosimo, and G. Arpino (2013)
Ann. Onc. 24, 2715-2724
   Abstract »    Full Text »    PDF »
Brinker possesses multiple mechanisms for repression because its primary co-repressor, Groucho, may be unavailable in some cell types.
P. Upadhyai and G. Campbell (2013)
Development 140, 4256-4265
   Abstract »    Full Text »    PDF »
{beta}-Transducin Repeat-containing Protein 1 ({beta}-TrCP1)-mediated Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) Protein Degradation Promotes Tumor Necrosis Factor {alpha} (TNF{alpha})-induced Inflammatory Gene Expression.
K.-S. Hsu and H.-Y. Kao (2013)
J. Biol. Chem. 288, 25375-25386
   Abstract »    Full Text »    PDF »
Emerging roles of the corepressors NCoR1 and SMRT in homeostasis.
A. Mottis, L. Mouchiroud, and J. Auwerx (2013)
Genes & Dev. 27, 819-835
   Abstract »    Full Text »    PDF »
Nuclear Translocation of MEK1 Triggers a Complex T Cell Response through the Corepressor Silencing Mediator of Retinoid and Thyroid Hormone Receptor.
L. Guo, C. Chen, Q. Liang, M. Z. Karim, M. M. Gorska, and R. Alam (2013)
J. Immunol. 190, 159-167
   Abstract »    Full Text »    PDF »
Regulated Clearance of Histone Deacetylase 3 Protects Independent Formation of Nuclear Receptor Corepressor Complexes.
C. Guo, C.-H. Gow, Y. Li, A. Gardner, S. Khan, and J. Zhang (2012)
J. Biol. Chem. 287, 12111-12120
   Abstract »    Full Text »    PDF »
Ligand-dependent Corepressor Acts as a Novel Androgen Receptor Corepressor, Inhibits Prostate Cancer Growth, and Is Functionally Inactivated by the Src Protein Kinase.
M. Asim, B. B. Hafeez, I. A. Siddiqui, C. Gerlach, M. Patz, H. Mukhtar, and A. Baniahmad (2011)
J. Biol. Chem. 286, 37108-37117
   Abstract »    Full Text »    PDF »
Transducin {beta}-Like Protein 1 Recruits Nuclear Factor {kappa}B to the Target Gene Promoter for Transcriptional Activation.
S. Ramadoss, J. Li, X. Ding, K. Al Hezaimi, and C.-Y. Wang (2011)
Mol. Cell. Biol. 31, 924-934
   Abstract »    Full Text »    PDF »
Differential Requirement of Histone Acetylase and Deacetylase Activities for IRF5-Mediated Proinflammatory Cytokine Expression.
D. Feng, N. Sangster-Guity, R. Stone, J. Korczeniewska, M. E. Mancl, P. Fitzgerald-Bocarsly, and B. J. Barnes (2010)
J. Immunol. 185, 6003-6012
   Abstract »    Full Text »    PDF »
Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens.
M. Eisold, M. Asim, H. Eskelinen, T. Linke, and A. Baniahmad (2009)
J. Mol. Endocrinol. 42, 429-435
   Abstract »    Full Text »    PDF »
Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways.
S. Ghisletti, W. Huang, K. Jepsen, C. Benner, G. Hardiman, M. G. Rosenfeld, and C. K. Glass (2009)
Genes & Dev. 23, 681-693
   Abstract »    Full Text »    PDF »
Activation of TORC1 Transcriptional Coactivator through MEKK1-induced Phosphorylation.
Y.-T. Siu, Y.-P. Ching, and D.-Y. Jin (2008)
Mol. Biol. Cell 19, 4750-4761
   Abstract »    Full Text »    PDF »
Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B cells.
J. M. Polo, W. Ci, J. D. Licht, and A. Melnick (2008)
Blood 112, 644-651
   Abstract »    Full Text »    PDF »
Estrogen Receptors: How Do They Signal and What Are Their Targets.
N. Heldring, A. Pike, S. Andersson, J. Matthews, G. Cheng, J. Hartman, M. Tujague, A. Strom, E. Treuter, M. Warner, et al. (2007)
Physiol Rev 87, 905-931
   Abstract »    Full Text »    PDF »
MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.
M. Milella, M. Konopleva, C. M. Precupanu, Y. Tabe, M. R. Ricciardi, C. Gregorj, S. J. Collins, B. Z. Carter, C. D'Angelo, M. T. Petrucci, et al. (2007)
Blood 109, 2121-2129
   Abstract »    Full Text »    PDF »
Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer.
V. Fernandez-Majada, C. Aguilera, A. Villanueva, F. Vilardell, A. Robert-Moreno, A. Aytes, F. X. Real, G. Capella, M. W. Mayo, L. Espinosa, et al. (2007)
PNAS 104, 276-281
   Abstract »    Full Text »    PDF »
Overview of Nomenclature of Nuclear Receptors.
P. Germain, B. Staels, C. Dacquet, M. Spedding, and V. Laudet (2006)
Pharmacol. Rev. 58, 685-704
   Abstract »    Full Text »    PDF »
Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response.
M. G. Rosenfeld, V. V. Lunyak, and C. K. Glass (2006)
Genes & Dev. 20, 1405-1428
   Abstract »    Full Text »    PDF »
Analysis of the Transcription Factor WUSCHEL and Its Functional Homologue in Antirrhinum Reveals a Potential Mechanism for Their Roles in Meristem Maintenance.
M. Kieffer, Y. Stern, H. Cook, E. Clerici, C. Maulbetsch, T. Laux, and B. Davies (2006)
PLANT CELL 18, 560-573
   Abstract »    Full Text »    PDF »
Regulation and Binding of Pregnane X Receptor by Nuclear Receptor Corepressor Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT).
D. R. Johnson, C.-W. Li, L.-Y. Chen, J. C. Ghosh, and J. D. Chen (2006)
Mol. Pharmacol. 69, 99-108
   Abstract »    Full Text »    PDF »
Activation of TRAP/Mediator Subunit TRAP220/Med1 Is Regulated by Mitogen-Activated Protein Kinase-Dependent Phosphorylation.
P. K. Pandey, T. S. Udayakumar, X. Lin, D. Sharma, P. S. Shapiro, and J. D. Fondell (2005)
Mol. Cell. Biol. 25, 10695-10710
   Abstract »    Full Text »    PDF »
Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy.
X. Cui, R. Schiff, G. Arpino, C. K. Osborne, and A. V. Lee (2005)
J. Clin. Oncol. 23, 7721-7735
   Abstract »    Full Text »    PDF »
Benzodithiophenes Potentiate Differentiation of Acute Promyelocytic Leukemia Cells by Lowering the Threshold for Ligand-Mediated Corepressor/Coactivator Exchange with Retinoic Acid Receptor {alpha} and Enhancing Changes in all-trans-Retinoic Acid-Regulated Gene Expression.
K. Xu, F. Guidez, A. Glasow, D. Chung, K. Petrie, K. Stegmaier, K.-K. Wang, J. Zhang, Y. Jing, A. Zelent, et al. (2005)
Cancer Res. 65, 7856-7865
   Abstract »    Full Text »    PDF »
Transcriptional Activity of Sp1 Is Regulated by Molecular Interactions between the Zinc Finger DNA Binding Domain and the Inhibitory Domain with Corepressors, and This Interaction Is Modulated by MEK.
J.-A. Lee, D.-C. Suh, J.-E. Kang, M.-H. Kim, H. Park, M.-N. Lee, J.-M. Kim, B.-N. Jeon, H.-E. Roh, M.-Y. Yu, et al. (2005)
J. Biol. Chem. 280, 28061-28071
   Abstract »    Full Text »    PDF »
The Clinical Relevance of Steroid Hormone Receptor Corepressors.
R. Kumar, A. E. Gururaj, R. K. Vadlamudi, and S. K. Rayala (2005)
Clin. Cancer Res. 11, 2822-2831
   Abstract »    Full Text »    PDF »
Estrogen-Receptor Biology: Continuing Progress and Therapeutic Implications.
C. K. Osborne and R. Schiff (2005)
J. Clin. Oncol. 23, 1616-1622
   Full Text »    PDF »
Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer.
C. J. Fabian and B. F. Kimler (2005)
J. Clin. Oncol. 23, 1644-1655
   Full Text »    PDF »
Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors.
M. L. Goodson, B. A. Jonas, and M. L. Privalsky (2005)
J. Biol. Chem. 280, 7493-7503
   Abstract »    Full Text »    PDF »
Crosstalk between Estrogen Receptor and Growth Factor Receptor Pathways as a Cause for Endocrine Therapy Resistance in Breast Cancer.
C. K. Osborne, J. Shou, S. Massarweh, and R. Schiff (2005)
Clin. Cancer Res. 11, 865s-870s
   Abstract »    Full Text »    PDF »
Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways.
A. Glasow, N. Prodromou, K. Xu, M. von Lindern, and A. Zelent (2005)
Blood 105, 341-349
   Abstract »    Full Text »    PDF »
SMRT and N-CoR Corepressors Are Regulated by Distinct Kinase Signaling Pathways.
B. A. Jonas and M. L. Privalsky (2004)
J. Biol. Chem. 279, 54676-54686
   Abstract »    Full Text »    PDF »
Mechanisms of tamoxifen resistance.
A. Ring and M. Dowsett (2004)
Endocr. Relat. Cancer 11, 643-658
   Abstract »    Full Text »    PDF »
Localized Feedback Phosphorylation of Ste5p Scaffold by Associated MAPK Cascade.
A. Flotho, D. M. Simpson, M. Qi, and E. A. Elion (2004)
J. Biol. Chem. 279, 47391-47401
   Abstract »    Full Text »    PDF »
The Thyroid Hormone Receptor Is a Suppressor of ras-Mediated Transcription, Proliferation, and Transformation.
S. Garcia-Silva and A. Aranda (2004)
Mol. Cell. Biol. 24, 7514-7523
   Abstract »    Full Text »    PDF »
Mechanisms of Tamoxifen Resistance: Increased Estrogen Receptor-HER2/neu Cross-Talk in ER/HER2-Positive Breast Cancer.
J. Shou, S. Massarweh, C. K. Osborne, A. E. Wakeling, S. Ali, H. Weiss, and R. Schiff (2004)
J Natl Cancer Inst 96, 926-935
   Abstract »    Full Text »    PDF »
Coordination of Cell Signaling, Chromatin Remodeling, Histone Modifications, and Regulator Recruitment in Human Matrix Metalloproteinase 9 Gene Transcription.
Z. Ma, R. C. Shah, M. J. Chang, and E. N. Benveniste (2004)
Mol. Cell. Biol. 24, 5496-5509
   Abstract »    Full Text »    PDF »
The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT.
S. Takahashi, M. J. McConnell, H. Harigae, M. Kaku, T. Sasaki, A. M. Melnick, and J. D. Licht (2004)
Blood 103, 4650-4658
   Abstract »    Full Text »    PDF »
rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development.
J. Gates, G. Lam, J. A. Ortiz, R. Losson, and C. S. Thummel (2004)
Development 131, 25-36
   Abstract »    Full Text »    PDF »
The T-box Factor Tpit Recruits SRC/p160 Co-activators and Mediates Hormone Action.
M. Maira, C. Couture, G. Le Martelot, A.-M. Pulichino, S. Bilodeau, and J. Drouin (2003)
J. Biol. Chem. 278, 46523-46532
   Abstract »    Full Text »    PDF »
v-SRC Specifically Regulates the Nucleo-cytoplasmic Delocalization of the Major Isoform of TEL (ETV6).
R. G. Lopez, C. Carron, and J. Ghysdael (2003)
J. Biol. Chem. 278, 41316-41325
   Abstract »    Full Text »    PDF »
Protein Kinase C{theta} Modulates Nuclear Receptor-Corepressor Interaction during T Cell Activation.
M. Ishaq, G. DeGray, and V. Natarajan (2003)
J. Biol. Chem. 278, 39296-39302
   Abstract »    Full Text »    PDF »
p27Kip1 Induces Quiescence and Growth Factor Insensitivity in Tamoxifen-treated Breast Cancer Cells.
J. S. Carroll, D. K. Lynch, A. Swarbrick, J.-M. Renoir, B. Sarcevic, R. J. Daly, E. A. Musgrove, and R. L. Sutherland (2003)
Cancer Res. 63, 4322-4326
   Abstract »    Full Text »    PDF »
Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression.
B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky (2003)
Mol. Cell. Biol. 23, 2844-2858
   Abstract »    Full Text »    PDF »
Ikappa Balpha and p65 Regulate the Cytoplasmic Shuttling of Nuclear Corepressors: Cross-talk between Notch and NFkappa B Pathways.
L. Espinosa, J. Ingles-Esteve, A. Robert-Moreno, and A. Bigas (2003)
Mol. Biol. Cell 14, 491-502
   Abstract »    Full Text »    PDF »
Breast Cancer Endocrine Resistance: How Growth Factor Signaling and Estrogen Receptor Coregulators Modulate Response.
R. Schiff, S. Massarweh, J. Shou, and C. K. Osborne (2003)
Clin. Cancer Res. 9, 447s-454s
   Abstract »    Full Text »
ErbB (HER) Receptors Can Abrogate Antiestrogen Action in Human Breast Cancer by Multiple Signaling Mechanisms.
H. Kurokawa and C. L. Arteaga (2003)
Clin. Cancer Res. 9, 511s-515s
   Abstract »    Full Text »
Developmentally Regulated N-terminal Variants of the Nuclear Receptor Hepatocyte Nuclear Factor 4alpha Mediate Multiple Interactions through Coactivator and Corepressor-Histone Deacetylase Complexes.
M. E. Torres-Padilla, F. M. Sladek, and M. C. Weiss (2002)
J. Biol. Chem. 277, 44677-44687
   Abstract »    Full Text »    PDF »
Functional Evidence for Retinoid X Receptor (RXR) as a Nonsilent Partner in the Thyroid Hormone Receptor/RXR Heterodimer.
D. Li, T. Li, F. Wang, H. Tian, and H. H. Samuels (2002)
Mol. Cell. Biol. 22, 5782-5792
   Abstract »    Full Text »    PDF »
Regulation of Estrogen Receptor Nuclear Export by Ligand-Induced and p38-Mediated Receptor Phosphorylation.
H. Lee and W. Bai (2002)
Mol. Cell. Biol. 22, 5835-5845
   Abstract »    Full Text »    PDF »
Signaling disrupts mSin3A binding to the Mad1-like Sin3-interacting domain of TIEG2, an Sp1-like repressor.
V. Ellenrieder, J.-S. Zhang, J. Kaczynski, and R. Urrutia (2002)
EMBO J. 21, 2451-2460
   Abstract »    Full Text »    PDF »
Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.
S. Barolo and J. W. Posakony (2002)
Genes & Dev. 16, 1167-1181
   Full Text »    PDF »
Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4{alpha}1: Modulation by the F Domain.
M. D. Ruse Jr., M. L. Privalsky, and F. M. Sladek (2002)
Mol. Cell. Biol. 22, 1626-1638
   Abstract »    Full Text »    PDF »
Multi-parameter analysis of the kinetics of NF-{kappa}B signalling and transcription in single living cells.
G. Nelson, L. Paraoan, D. G. Spiller, G. J. C. Wilde, M. A. Browne, P. K. Djali, J. F. Unitt, E. Sullivan, E. Floettmann, and M. R. H. White (2002)
J. Cell Sci. 115, 1137-1148
   Abstract »    Full Text »    PDF »
p65-NF{kappa}B synergizes with Notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR.
L. Espinosa, S. Santos, J. Ingles-Esteve, P. Munoz-Canoves, and A. Bigas (2002)
J. Cell Sci. 115, 1295-1303
   Abstract »    Full Text »    PDF »
Biological roles and mechanistic actions of co-repressor complexes.
K. Jepsen and M. G. Rosenfeld (2002)
J. Cell Sci. 115, 689-698
   Abstract »    Full Text »    PDF »
The cytokines IL-3 and GM-CSF regulate the transcriptional activity of retinoic acid receptors in different in vitro models of myeloid differentiation.
B. S. Johnson, L. Mueller, J. Si, and S. J. Collins (2002)
Blood 99, 746-753
   Abstract »    Full Text »    PDF »
Silencing Mediator of Retinoid and Thyroid Hormone Receptors and Activating Signal Cointegrator-2 as Transcriptional Coregulators of the Orphan Nuclear Receptor Nur77.
Y. C. Sohn, E. Kwak, Y. Na, J. W. Lee, and S.-K. Lee (2001)
J. Biol. Chem. 276, 43734-43739
   Abstract »    Full Text »    PDF »
S. M. Yoh and M. L. Privalsky (2001)
J. Biol. Chem. 276, 16857-16867
   Abstract »    Full Text »    PDF »
Ca2+/Calmodulin-dependent Protein Kinase IV Stimulates Nuclear Factor-kappa B Transactivation via Phosphorylation of the p65 Subunit.
M. K. Jang, Y. H. Goo, Y. C. Sohn, Y. S. Kim, S.-K. Lee, H. Kang, J. Cheong, and J. W. Lee (2001)
J. Biol. Chem. 276, 20005-20010
   Abstract »    Full Text »    PDF »
Transgenic Targeting of a Dominant Negative Corepressor to Liver Blocks Basal Repression by Thyroid Hormone Receptor and Increases Cell Proliferation.
X. Feng, Y. Jiang, P. Meltzer, and P. M. Yen (2001)
J. Biol. Chem. 276, 15066-15072
   Abstract »    Full Text »    PDF »
SMRTe Inhibits MEF2C Transcriptional Activation by Targeting HDAC4 and 5 to Nuclear Domains.
X. Wu, H. Li, E.-J. Park, and J. D. Chen (2001)
J. Biol. Chem. 276, 24177-24185
   Abstract »    Full Text »    PDF »
Coregulator Codes of Transcriptional Regulation by Nuclear Receptors.
M. G. Rosenfeld and C. K. Glass (2001)
J. Biol. Chem. 276, 36865-36868
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882