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 García-Silva, S.
Right arrow Articles by Aranda, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by García-Silva, S.
Right arrow Articles by Aranda, A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2004, p. 7514-7523, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7514-7523.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Thyroid Hormone Receptor Is a Suppressor of ras-Mediated Transcription, Proliferation, and Transformation

Susana García-Silva and Ana Aranda*

Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain

Received 12 March 2004/ Returned for modification 4 April 2004/ Accepted 1 June 2004

The thyroid hormone triiodothyronine (T3) has a profound effect on growth, differentiation, and metabolism in higher organisms. Here we demonstrate that T3 inhibits ras-induced proliferation in neuroblastoma cells and blocks induction of cyclin D1 expression by the oncogene. The hormone, at physiological concentrations, strongly antagonizes the transcriptional response mediated by the Ras/mitogen-activated protein kinase/ribosomal-S6 subunit kinase (Rsk) signaling pathway in cells expressing thyroid hormone receptors (TRs). T3 blocks the response to the oncogenic forms of the three ras isoforms (H-, K-, and N-ras) and both TR{alpha} and TRß can mediate this action. The main target for induction of cyclin D1 transcription by oncogenic ras in neuroblastoma cells is a cyclic AMP response element (CRE) located in proximal promoter sequences, and T3 represses the transcriptional activity of b-Zip transcription factors such as CREB (CRE-binding protein) or ATF-2 (activation transcription factor 2) that are direct targets of Rsk2 and bind to this sequence. The hormone also blocks fibroblast transformation by oncogenic ras when TR is expressed. Furthermore, TRs act as suppressors of tumor formation by the oncogene in vivo in nude mice. The TRß isoform has stronger antitransforming properties than the {alpha} isoform and can inhibit tumorigenesis even in hypothyroid mice. These results show the existence of a previously unrecognized transcriptional cross talk between the TRs and the ras oncogene which influences relevant processes such as cell proliferation, transformation, or tumorigenesis.

* Corresponding author. Mailing address: Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain. Phone: 34-91-5854453. Fax: 34-91-5854401. E-mail: aaranda{at}iib.uam.es.

Molecular and Cellular Biology, September 2004, p. 7514-7523, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7514-7523.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sanchez-Pacheco, A., Martinez-Iglesias, O., Mendez-Pertuz, M., Aranda, A. (2009). Residues K128, 132, and 134 in the Thyroid Hormone Receptor-{alpha} Are Essential for Receptor Acetylation and Activity. Endocrinology 150: 5143-5152 [Abstract] [Full Text]  
  • Martinez-Iglesias, O., Garcia-Silva, S., Tenbaum, S. P., Regadera, J., Larcher, F., Paramio, J. M., Vennstrom, B., Aranda, A. (2009). Thyroid Hormone Receptor {beta}1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis. Cancer Res. 69: 501-509 [Abstract] [Full Text]  
  • Chiloeches, A., Sanchez-Pacheco, A., Gil-Araujo, B., Aranda, A., Lasa, M. (2008). Thyroid Hormone-Mediated Activation of the ERK/Dual Specificity Phosphatase 1 Pathway Augments the Apoptosis of GH4C1 Cells by Down-Regulating Nuclear Factor-{kappa}B Activity. Mol. Endocrinol. 22: 2466-2480 [Abstract] [Full Text]  
  • De los Santos, M., Martinez-Iglesias, O., Aranda, A. (2007). Anti-estrogenic actions of histone deacetylase inhibitors in MCF-7 breast cancer cells. Endocr Relat Cancer 14: 1021-1028 [Abstract] [Full Text]  
  • De los Santos, M., Zambrano, A., Sanchez-Pacheco, A., Aranda, A. (2007). Histone Deacetylase Inhibitors Regulate Retinoic Acid Receptor {beta} Expression in Neuroblastoma Cells by Both Transcriptional and Posttranscriptional Mechanisms. Mol. Endocrinol. 21: 2416-2426 [Abstract] [Full Text]  
  • Hassani, Z., Francois, J.-C., Alfama, G., Dubois, G. M., Paris, M., Giovannangeli, C., Demeneix, B. A. (2007). A hybrid CMV-H1 construct improves efficiency of PEI-delivered shRNA in the mouse brain. Nucleic Acids Res 35: e65-e65 [Abstract] [Full Text]  
  • De los Santos, M., Zambrano, A., Aranda, A. (2007). Combined effects of retinoic acid and histone deacetylase inhibitors on human neuroblastoma SH-SY5Y cells. Molecular Cancer Therapeutics 6: 1425-1432 [Abstract] [Full Text]  
  • Flamant, F., Gauthier, K., Samarut, J. (2007). Thyroid Hormones Signaling Is Getting More Complex: STORMs Are Coming. Mol. Endocrinol. 21: 321-333 [Abstract] [Full Text]  
  • Dronadula, N., Rizvi, F., Blaskova, E., Li, Q., Rao, G. N. (2006). Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility. J. Lipid Res. 47: 767-777 [Abstract] [Full Text]  
  • Ledda-Columbano, G. M., Molotzu, F., Pibiri, M., Cossu, C., Perra, A., Columbano, A. (2006). Thyroid hormone induces cyclin D1 nuclear translocation and DNA synthesis in adult rat cardiomyocytes. FASEB J. 20: 87-94 [Abstract] [Full Text]  
  • Conde, I., Paniagua, R., Zamora, J., Blanquez, M. J., Fraile, B., Ruiz, A., Arenas, M. I. (2006). Influence of thyroid hormone receptors on breast cancer cell proliferation. Ann Oncol 17: 60-64 [Abstract] [Full Text]  
  • French, D., Wilkinson, M. R., Yang, W., de Chaisemartin, L., Cook, E. H., Das, S., Ratain, M. J., Evans, W. E., Downing, J. R., Pui, C.-H., Relling, M. V. (2005). Global gene expression as a function of germline genetic variation. Hum Mol Genet 14: 1621-1629 [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»