2024-03-29T11:14:09Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/245492022-05-05T07:43:21Zcom_10261_22com_10261_1col_10261_275
The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation
García-Silva, Susana
Aranda, Ana
10 pages, 9 figures.
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 TRalpha and TRbeta 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 TRbeta 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.
This study was supported by grants from the Association for International
Cancer Research (02-101), Comunidad de Madrid (08.1/
0047.1/2001), the Ministerio de Ciencia y Tecnología (BMC2001-
2275), and the Fundación La Caixa.
Peer reviewed
2010-05-20T13:07:51Z
2010-05-20T13:07:51Z
2004-09
artículo
http://purl.org/coar/resource_type/c_6501
Molecular and Cellular Biology 24(17): 7514-7523 (2004)
0270-7306
http://hdl.handle.net/10261/24549
10.1128/MCB.24.17.7514-7523.2004
15314161
en
http://dx.doi.org/10.1128/MCB.24.17.7514-7523.2004
none
457687 bytes
application/pdf
American Society for Microbiology