Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing

Rj, Koenig; Ma, Lazar; Ra, Hodin; Brent, GA; Larsen, Peder Olesen; Ww, Chin; Dd, Moore

doi:10.1038/337659a0

Cited by 420 publications

(173 citation statements)

References 28 publications

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“…The most 5' one drives the expression of two isoforms, contiguous in their 5' end but di ering in their 3' region. Only the TRa1 isoform is translated in a true hormone receptor, whereas the TRa2 isoform is unable to bind thyroid hormone (T3) and thus acts as a natural dominant negative variant (Koenig et al, 1989). In addition, an internal promoter produces trucated proteins which also act as transdominant negative .…”

Section: Introductionmentioning

confidence: 99%

Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

et al. 1998

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The superfamily of nuclear receptors comprises transcription factors that depend on a ligand for their activity. In addition, the superfamily includes a number of orphan receptors, for which no ligand is known. We report here that the orphan receptor estrogen receptor related alpha receptor (ERRa) stimulates the expression of the thyroid hormone receptor alpha (TRa) gene promoter. We characterized a responsive site that is both necessary and su cient for ERRa-induced transactivation. In addition, we show that both TRa and ERRa are coexpressed in embryonic intestine, brown fat and heart as well as in the adult gonads. In the testis, expression of both receptors can be found in the seminiferous tubes where it is totally restricted to spermatocytes I. Altogether this suggests that TRa is an in vivo target of ERRa.

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Section: Introductionmentioning

confidence: 99%

Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

et al. 1998

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“…Furthermore, these isoforms act as homodimers or heterodimers together with other members of the nuclear receptor family (52,53) and, depending on the targeted genes and the presence of their ligand, coactivators or corepressors either activate or repress gene transcription (17,(53)(54)(55). T 3 nuclear receptor isoforms can also inhibit one another's transcriptional activities (22,56). Finally, T3R isoforms specifically retro-control thyroid hormone production in a complex fashion.…”

Section: The Role Of the Different Isoforms In The Immune System Devementioning

confidence: 99%

Effects of T3Rα1 and T3Rα2 Gene Deletion on T and B Lymphocyte Development

Arpin

Pihlgren

Fraichard

et al. 2000

The Journal of Immunology

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Thyroid hormones bind to several nuclear receptors encoded by T3Rα and T3Rβ genes. There is now accumulating evidence that thyroid hormones act on the immune system. Indeed, mice deficient for thyroid hormones show a reduction in lymphocyte production. However, the mechanisms involved and, in particular, the role of the different thyroid hormone receptors in lymphocyte development have not been investigated. To address that question, we have studied lymphocyte development in mice deficient for the T3Rα1 and T3Rα2 gene products. A strong decrease in spleen cell numbers was found compared with wild-type littermates, B lymphocytes being more severely affected than T lymphocytes. A significant decrease in splenic macrophage and granulocyte numbers was also found. In bone marrow, a reduction in CD45+/IgM− pro/pre-B cell numbers was found in these mice compared with wild-type littermates. This decrease seems to result from a proliferation defect, as CD45+/IgM− cells incorporate less 5-bromo-2′-deoxyuridine in vivo. To define the origin of the bone marrow development defect, chimeric animals between T3Rα−/− and Rag1−/− mice were generated. Results indicate that for B cells the control of the population size by T3Rα1 and T3Rα2 is intrinsic. Altogether, these results show that T3Rα1 or T3Rα2 gene products are implicated in the control of the B cell pool size.

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“…rev-erbA␣ and TR␣ 2 mRNAs are complementary for a stretch of 269 nucleotides because of bidirectional transcription of a partially common exon. The peculiar arrangement of the rev-erbA␣ gene has led to the suggestion that its transcription could interfere with the expression of the thyroid hormone receptor (21,27) by regulating alternative processing of ␣ 1 and ␣ 2 mRNAs in vitro by an antisense mechanism (36). Thus relatively modest changes in splice site selection could cause major changes in cellular T 3 responsiveness (27).…”

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confidence: 99%

Aberrant expression of myosin isoforms in skeletal muscles from mice lacking therev-erbAαorphan receptor gene

Pircher¹,

Chomez²,

Yu³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erbA␣ orphan receptor gene. Am J Physiol Regul Integr Comp Physiol 288: R482-R490, 2005. First published September 16, 2004; doi:10.1152/ajpregu.00690.2003.-The rev-erbA␣ orphan protein belongs to the steroid nuclear receptor superfamily. No ligand has been identified for this protein, and little is known of its function in development or physiology. In this study, we focus on 1) the distribution of the rev-erbA␣ protein in adult fast-and slow-twitch skeletal muscles and muscle fibers and 2) how the rev-erbA␣ protein influences myosin heavy chain (MyHC) isoform expression in mice heterozygous (ϩ/Ϫ) and homozygous (Ϫ/Ϫ) for a rev-erbA␣ protein null allele. In the fast-twitch extensor digitorum longus muscle, rev-erbA␣ protein expression was linked to muscle fiber type; however, MyHC isoform expression did not differ between wild-type, ϩ/Ϫ, or Ϫ/Ϫ mice. In the slow-twitch soleus muscle, the link between rev-erbA␣ protein and MyHC isoform expression was more complex than in the extensor digitorum longus. Here, a significantly higher relative amount of the ␤/slow (type I) MyHC isoform was observed in both rev-erbA␣ Ϫ/Ϫ and ϩ/Ϫ mice vs. that shown in wild-type controls. A role for the ratio of thyroid hormone receptor proteins ␣ 1 to ␣2 in modulating MyHC isoform expression can be ruled out because no differences were seen in MyHC isoform expression between thyroid hormone receptor ␣ 2-deficient mice (heterozygous and homozygous) and wild-type mice. Therefore, our data are compatible with the rev-erbA␣ protein playing an important role in the regulation of skeletal muscle MyHC isoform expression. orphan nuclear receptors; thyroid hormone; fast-and slow-twitch muscle THE VARIABLE EXPRESSION OF myofibrillar protein isoforms is a major determinant of the contractile properties and ATPase activities of skeletal and myocardial fibers (3, 50). The myosin heavy chain (MyHC) molecule is the most abundant myofibrillar protein and is encoded by a multigene family consisting of several members (35). Several isoforms have now been described in rodent skeletal muscles, including one slow isoform (type I or ␤/slow), three fast (IIa, IIx/d, and IIb), and two developmental (embryonic and neonatal/perinatal/fetal) isoforms, which are all coded by distinct genes (50). Four other MyHC isoforms, slow tonic, superfast IIm, ␣-cardiac-like, and extraocular myosin, are expressed in a few specialized muscles (7, 50). Despite their similarity in primary structure, the expression of different MyHC isoforms is precisely regulated in a tissue-specific and developmental stage-specific manner (50, 52). In addition, innervation patterns (33, 45, 46), altered physiological stimuli (34, 46), and various hormones (19) are known to have a significant impact on MyHC isoform expression.Skeletal muscle is a major target for hormone action. Thyroid hormone is one of the most potent regulators of skeletal muscle MyHC isoform expression in mammals, and it has been suggested...

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Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing

Cited by 420 publications

References 28 publications

Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

Effects of T3Rα1 and T3Rα2 Gene Deletion on T and B Lymphocyte Development

Aberrant expression of myosin isoforms in skeletal muscles from mice lacking therev-erbAαorphan receptor gene

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