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Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors

AuthorsTolón, Rosa M.; Castillo, Ana I. CSIC; Jiménez Lara, Ana M. CSIC ORCID ; Aranda, Ana CSIC ORCID
Issue DateDec-2000
PublisherAmerican Society for Microbiology
CitationMolecular and Cellular Biology 20(23): 8793-8802 (2000)
AbstractThe vitamin D receptor (VDR) normally functions as a ligand-dependent transcriptional activator. Here we show that, in the presence of Ets-1, VDR stimulates the prolactin promoter in a ligand-independent manner, behaving as a constitutive activator. Mutations in the AF2 domain abolish vitamin D-dependent transactivation but do not affect constitutive activation by Ets-1. Therefore, in contrast with the actions of vitamin D, activation by Ets-1 is independent of the AF2 domain. Ets-1 also conferred a ligand-independent activation to the estrogen receptor and to peroxisome proliferator-activated receptor alpha. In addition, Ets-1 cooperated with the unliganded receptors to stimulate the activity of reporter constructs containing consensus response elements fused to the thymidine kinase promoter. There is a direct interaction of the receptors with Ets-1 which requires the DNA binding domains of both proteins. Interaction with Ets-1 induces a conformational change in VDR which can be detected by an increased resistance to proteolytic digestion. Furthermore, a retinoid X receptor-VDR heterodimer in which both receptors lack the core C-terminal AF2 domain can recruit coactivators in the presence, but not in the absence, of Ets-1. This suggests that Ets-1 induces a conformational change in the receptor which creates an active interaction surface with coactivators even in the AF2-defective mutants. These results demonstrate the existence of a novel mechanism, alternative to ligand binding, which can convert an unliganded receptor from an inactive state into a competent transcriptional activator.
Description10 pages, 10 figures.
Publisher version (URL)http://mcb.asm.org/cgi/content/abstract/20/23/8793
Appears in Collections:(IIBM) Artículos
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