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Differential recruitment of nuclear coregulators directs the isoform-dependent action of mutant thyroid hormone receptors.

ABSTRACT: Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TR?1 and TR?1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TR?1 (Thra1(PV) mice) or ?1 (Thrb(PV) mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-dependent functions in vivo. Here we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that distinct 33 nuclear proteins including nuclear receptor corepressor (NCoR1) and six other proteins preferentially associated with TR?1PV or TR?1PV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is subtype dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of Thra1(PV) and Thrb(PV) mice was further explored. NCoR1 preferentially interacted with TR?1PV rather than with TR?1PV. NCoR1 was recruited more avidly to the thyroid hormone response element-bound TR?1PV than to TR?1PV in the promoter of the CCAAT/enhancer-binding protein ? gene to repress its expression in the liver of Thra1(PV) mice, but not in Thrb(PV) mice. This preferential recruitment of NCoR1 by mutant isoforms could contribute, at least in part, to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins.

SUBMITTER: Fozzatti L

PROVIDER: S-EPMC3100599 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Differential recruitment of nuclear coregulators directs the isoform-dependent action of mutant thyroid hormone receptors.

Fozzatti Laura L Lu Changxue C Kim Dong-Wook DW Cheng Sheue-yann SY

Molecular endocrinology (Baltimore, Md.) 20110407 6

Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TRα1 and TRβ1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TRα1 (Thra1(PV) mice) or β1 (Thrb(PV) mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-depend ...[more]

PMID: 21474540

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Project description:BackgroundEndometriosis is defined as the colonization and growth of endometrial tissue at anatomic sites outside the uterine cavity. Up to 15% of reproductive-aged women in the USA suffer from painful symptoms of endometriosis, such as infertility, pelvic pain, menstrual cycle abnormalities and increased risk of certain cancers. However, many of the current clinical treatments for endometriosis are not sufficiently effective and yield unacceptable side effects. There is clearly an urgent need to identify new molecular mechanisms that critically underpin the initiation and progression of endometriosis in order to develop more specific and effective therapeutics which lack the side effects of current therapies. The aim of this review is to discuss how nuclear receptors (NRs) and their coregulators promote the progression of endometriosis. Understanding the pathogenic molecular mechanisms for the genesis and maintenance of endometriosis as modulated by NRs and coregulators can reveal new therapeutic targets for alternative endometriosis treatments.MethodsThis review was prepared using published gene expression microarray data sets obtained from patients with endometriosis and published literature on NRs and their coregulators that deal with endometriosis progression. Using the above observations, our current understanding of how NRs and NR coregulators are involved in the progression of endometriosis is summarized.ResultsAberrant levels of NRs and NR coregulators in ectopic endometriosis lesions are associated with the progression of endometriosis. As an example, endometriotic cell-specific alterations in gene expression are correlated with a differential methylation status of the genome compared with the normal endometrium. These differential epigenetic regulations can generate favorable cell-specific NR and coregulator milieus for endometriosis progression. Genetic alterations, such as single nucleotide polymorphisms and insertion/deletion polymorphisms of NR and coregulator genes, are frequently detected in ectopic lesions compared with the normal endometrium. These genetic variations impart new molecular properties to NRs and coregulators to increase their capacity to stimulate progression of endometriosis. Finally, post-translational modifications of NR coregulators, such as proteolytic processing, generate endometriosis-specific isoforms. Compared with the unmodified coregulators, these coregulator isoforms have unique functions that enhance the pathogenesis of endometriosis.ConclusionsEpigenetic/genetic variations and posttranslational modifications of NRs and coregulators alter their original function so that they become potent 'drivers' of endometriosis progression.

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Differential recruitment of nuclear coregulators directs the isoform-dependent action of mutant thyroid hormone receptors.

Publications

Differential recruitment of nuclear coregulators directs the isoform-dependent action of mutant thyroid hormone receptors.

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