Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

Oncogene volume 30, pages 854–864 (2011)Cite this article

Subjects

Abstract

The thyroid hormone receptor (TR) is a suppressor of ras-mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRβ1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRβ1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRβ1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRβ1

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Anjum R, Blenis J . (2008). The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9: 747–758.

    Article  CAS  Google Scholar 

  • Aranda A, Pascual A . (2001). Nuclear hormone receptors and gene expression. Physiol Rev 81: 1269–1304.

    Article  CAS  Google Scholar 

  • Aranda A, Martínez-Iglesias O, Ruiz-Llorente L, García-Carpizo V, Zambrano A . (2009). Thyroid receptor: roles in cancer. Trends Endocrinol Metab 20: 319–324.

    Article  Google Scholar 

  • Berghagen H, Ragnhildstveit E, Krogsrud K, Thuestad G, Apriletti J, Saatcioglu F . (2002). Corepressor SMRT functions as a coactivator for thyroid hormone receptor T3Ralpha from a negative hormone response element. J Biol Chem 277: 49517–49522.

    Article  CAS  Google Scholar 

  • Bos JL . (1989). ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689.

    CAS  PubMed  Google Scholar 

  • Campbell SL, Khosravi-Far, Rossman KL, Clark GJ, Der CJ . (1998). Increasing complexity of Ras signaling. Oncogene 17: 1395–1413.

    Article  CAS  Google Scholar 

  • Castillo AI, Sanchez-Martinez R, Moreno JL, Martinez-Iglesias OA, Palacios D, Aranda A . (2004). A permissive retinoid X receptor/thyroid hormone receptor heterodimer allows stimulation of prolactin gene transcription by thyroid hormone and 9-cis-retinoic acid. Mol Cell Biol 24: 502–513.

    Article  CAS  Google Scholar 

  • Chan IH, Privalsky ML . 2006. Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs. Oncogene 25: 3576–3588.

    Article  CAS  Google Scholar 

  • Damm K, Beug H, Graf T, Vennström B . (1987). A single point mutation in erbA restores the erythroid transforming potency of a mutant avian erythroblastosis virus (AEV) defective in both erbA and erbB oncogenes. EMBO J 6: 675–682.

    Article  Google Scholar 

  • De Bosscher K, Van Craenenbroeck K, Meijer OC, Haegeman G . (2008). Selective transrepression versus transactivation mechanisms by glucocorticoid receptor modulators in stress and immune systems. Eur J Pharmacol 583: 290–302.

    Article  CAS  Google Scholar 

  • Feng W, Ribeiro RC, Wagner RL, Nguyen H, Apriletti JW, Fletterick RJ et al. (1998). Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280: 1747–1749.

    Article  CAS  Google Scholar 

  • Fernandez-Majada V, Pujadas J, Vilardell F, Capella G, Mayo MW, Bigas A et al. (2007). Aberrant cytoplasmic localization of N-CoR in colorectal tumors. Cell Cycle 6: 1748–1752.

    Article  CAS  Google Scholar 

  • Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ . (1994). Induction of cyclin D1 overexpression by activated ras. Oncogene 9: 3627–3633.

    CAS  PubMed  Google Scholar 

  • Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels H, Scanlan TS et al. (2006). International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev 58: 705–711.

    Article  CAS  Google Scholar 

  • Furumoto H, Ying H, Chandramouli GV, Zhao L, Walker RL, Meltzer PS et al. (2005). An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis. Mol Cell Biol 25: 124–135.

    Article  CAS  Google Scholar 

  • Furuya F, Lu C, Guigon CJ, Cheng SY . (2009). Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors. Steroids 74: 628–634.

    Article  CAS  Google Scholar 

  • Garcia-Silva S, Aranda A . (2004). The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. Mol Cell Biol 24: 7514–7523.

    Article  CAS  Google Scholar 

  • Hong SH, Yang Z, Privalsky ML . (2001). Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with its transcription factor partners, including the PML-retinoic acid receptor alpha oncoprotein found in human acute promyelocytic leukemia. Mol Cell Biol 21: 7172–7182.

    Article  CAS  Google Scholar 

  • Hörlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, Kurokawa R et al. (1995). Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377: 397–404.

    Article  Google Scholar 

  • Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A et al. (1998). Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 27: 951–958.

    Article  CAS  Google Scholar 

  • Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TMG, Schiff R et al. (1998). Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA 95: 2920–2925.

    Article  CAS  Google Scholar 

  • Lazar MA . (2003). Nuclear receptor corepressors. Nucl Recept Signal 1: e001.

    Article  Google Scholar 

  • Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ, Yang-Yen HF . (1995). Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol Cell Biol 15: 3654–3663.

    Article  CAS  Google Scholar 

  • Lowy DR, Willumsen BM . (1993). Function and regulation of ras. Annu Rev Biochem 62: 851–891.

    Article  CAS  Google Scholar 

  • Marimuthu A, Feng W, Tagami T, Nguyen H, Jameson JL, Fletterick RJ et al. (2002). TR surfaces and conformations required to bind nuclear receptor corepressor. Mol Endocrinol 16: 271–286.

    Article  CAS  Google Scholar 

  • Martínez-Iglesias O, García-Silva S, Tenbaun SP, Regadera J, Larcher F, Paramio JM et al. (2009a). The thyroid hormone receptor beta1 acts as a potent suppressor of tumor invasiveness and metastasis. Cancer Res 69: 501–509.

    Article  Google Scholar 

  • Martínez-Iglesias O, García-Silva S, Regadera J, Aranda A . (2009b). Hypothyroidism enhances tumor invasiveness and metastasis development. PLoS One 4: e6428.

    Article  Google Scholar 

  • Meier CA, Dickstein BM, Ashizawa K, McClaskey JH, Muchmore P, Ransom SC et al. (1992). Variable transcriptional activity and ligand binding of mutant beta 1 3,5,3’-triiodothyronine receptors from four families with generalized resistance to thyroid hormone. Mol Endocrinol 6: 248–258.

    CAS  PubMed  Google Scholar 

  • Mendez-Pertuz M, Sanchez-Pacheco A, Aranda A . (2003). The thyroid hormone receptor antagonizes CREB-mediated transcription. EMBO J 22: 3102–3112.

    Article  CAS  Google Scholar 

  • Pascual G, Glass CK . (2006). Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab 17: 321–327.

    Article  CAS  Google Scholar 

  • Perissi V, Staszewski LM, McInerney EM, Kurokawa R, Krones A, Rose DW et al. (1999). Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev 13: 3198–3208.

    Article  CAS  Google Scholar 

  • Peterson TJ, Karmakar S, Pace MC, Gao T, Smith CL . (2007). The silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full estrogen receptor alpha transcriptional activity. Mol Cell Biol 27: 5933–5948.

    Article  CAS  Google Scholar 

  • Pfahl M . (1993). Nuclear receptor/AP-1 interaction. Endocr Rev 14: 651–658.

    CAS  PubMed  Google Scholar 

  • Pissios P, Tzameli I, Kushner P, Moore DD . (2000). Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding. Mol Cell 6: 245–253.

    Article  CAS  Google Scholar 

  • Privalsky ML . (2004). The role of corepressors in transcriptional regulation by nuclear hormone receptors. Annu Rev Physiol 66: 315–360.

    Article  CAS  Google Scholar 

  • Robles AI, Rodriguez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P et al. (1998). Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev 12: 2469–2474.

    Article  CAS  Google Scholar 

  • Rogatsky I, Zarember KA, Yamamoto KR . (2001). Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J 20: 6071–6083.

    Article  CAS  Google Scholar 

  • Safer JD, Cohen RN, Hollenberg AN, Wondisford FE . (1998). Defective release of corepressor by hinge mutants of the thyroid hormone receptor found in patients with resistance to thyroid hormone. J Biol Chem 273: 30175–30182.

    Article  CAS  Google Scholar 

  • Sanchez-Martinez R, Castillo AI, Steinmeyer A, Aranda A . (2006). The retinoid X receptor ligand restores defective signalling by the vitamin D receptor. EMBO Rep 10: 1030–1034.

    Article  Google Scholar 

  • Song L, Zlobin A, Ghoshal P, Zhang Q, Houde C, Weijzen S et al. (2005). Alteration of SMRT tumor suppressor function in transformed non-Hodgkin lymphomas. Cancer Res 65: 4554–4561.

    Article  CAS  Google Scholar 

  • Suzuki H, Willingham MC, Cheng SY . (2002). Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid 12: 963–969.

    Article  CAS  Google Scholar 

  • Tagami T, Madison LD, Nagaya T, Jameson JL . (1997). Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. Mol Cell Biol 17: 2642–2648.

    Article  CAS  Google Scholar 

  • Xing J, Ginty DD, Greenberg ME . (1996). Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273: 959–963.

    Article  CAS  Google Scholar 

  • Yen PM . (2001). Physiological and molecular basis of thyroid hormone action. Physiol Rev 81: 1097–1142.

    Article  CAS  Google Scholar 

  • Zhu XG, Zhao L, Willingham MC, Cheng SY . (2010). Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma. Oncogene 29: 1909–1919.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to M Sánchez-Prieto and PA Chávez for technical help and to A Zambrano for TR mutants. This work was supported by Grant BFU2007–62402 from Ministerio de Educación y Ciencia, RD06/0020/0036 and Acción Transversal de Cáncer from the Fondo de Investigaciones Sanitarias and by the European Grant CRESCENDO (FP-018652).

Author information

Author notes

  1. S García-Silva, O Martínez-Iglesias and L Ruiz-Llorente: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrine and Nervous System Physiopathology, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain

    S García-Silva, O Martínez-Iglesias, L Ruiz-Llorente & A Aranda

Authors
  1. S García-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O Martínez-Iglesias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Ruiz-Llorente
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Aranda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Aranda.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

García-Silva, S., Martínez-Iglesias, O., Ruiz-Llorente, L. et al. Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors. Oncogene 30, 854–864 (2011). https://doi.org/10.1038/onc.2010.464

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.464

Keywords

This article is cited by

Search

Advanced search

Quick links