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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.



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