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J. Biol. Chem., Vol. 282, Issue 10, 7472-7481, March 9, 2007

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SRC-p300 Coactivator Complex Is Required for Thyroid Hormone-induced Amphibian Metamorphosis^*

From the Laboratory of Gene Regulation and Development, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Gene activation by the thyroid hormone (T3) receptor (TR) involves the recruitment of specific coactivator complexes to T3-responsive promoters. A large number of coactivators for TR have been isolated and characterized in vitro. However, their roles and functions in vivo during development have remained largely unknown. We have utilized metamorphosis in Xenopus laevis to study the role of these coactivators during post-embryonic development. Metamorphosis is totally dependent on the thyroid hormone, and TR mediates a vast majority, if not all, of the developmental effects of the hormone. We have previously shown that TR recruits the coactivator SRC3 (steroid receptor coactivator-3) and that coactivator recruitment is essential for metamorphosis. To determine whether SRCs are indeed required, we have analyzed the in vivo role of the histone acetyltransferase p300/CREB-binding protein (CBP), which was reported to be a component of the SRC·coactivator complexes. Chromatin immunoprecipitation revealed that p300 is recruited to T3-responsive promoters, implicating a role of p300 in TR function. Further, transgenic tadpoles overexpressing a dominant negative form of p300, F-dnp300, containing only the SRC-interacting domain, displayed arrested or delayed metamorphosis. Molecular analyses of the transgenic F-dnp300 animals showed that F-dnp300 was recruited by TR (displacing endogenous p300) and inhibited the expression of T3-responsive genes. Our results thus suggest that p300 and/or its related CBP is an essential component of the TR-signaling pathway in vivo and support the notion that p300/CBP and SRC proteins are part of the same coactivator complex in vivo during post-embryonic development.

Received for publication, August 9, 2006 , and in revised form, January 10, 2007.

^* This research was supported by the Intramural Research Program of the NICHD, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Neuroscience, Woods Basic Science Bldg., Rm. 807, 725 N. Wolfe St., Johns Hopkins University School of Medicine, Baltimore, MD 21205.

² To whom correspondence should be addressed: Bldg. 18T, Rm. 106, LGRD, NICHD, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-402-1004; Fax: 301-402-1323; E-mail: shi{at}helix.nih.gov.

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This article has been cited by other articles:

				H. Matsuda, B. D. Paul, C. Y. Choi, T. Hasebe, and Y.-B. Shi Novel Functions of Protein Arginine Methyltransferase 1 in Thyroid Hormone Receptor-Mediated Transcription and in the Regulation of Metamorphic Rate in Xenopus laevis Mol. Cell. Biol., February 1, 2009; 29(3): 745 - 757. [Abstract] [Full Text] [PDF]