The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate

Dentice, Monica; Bandyopadhyay, Amitabha; Gereben, Balázs; Callebaut, Isabelle; Christoffolete, Marcelo A.; Kim, Brian W.; Nissim, Sahar; Mornon, J.‐P.; Zavacki, Ann Marie; Zeöld, Anikó; Capelo, Luciane Portas; Curcio-Morelli, Cyntia; Ribeiro, Rogério Silicani; Harney, John W.; Tabin, Clifford J.; Bianco, Antonio C.

doi:10.1038/ncb1272

Cited by 203 publications

(204 citation statements)

References 35 publications

(1 reference statement)

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“…3d). The Shh-mediated induction of D3 significantly extends the concept that Shh induces a local thyroid hormone attenuation in the microenvironment, already independent of, but synergizing with its reduction of D2 activity (7). The fact that Shh induces D3, thereby preventing T4 activation as well as directly inactivating T3, whether it is generated from T4 or comes from the thyroid gland through the circulation, suggests that abrogating thyroid hormone signaling in a time-and cell type-specific fashion is essential to the biological effect of this morphogen.…”

Section: Resultsmentioning

confidence: 80%

“…New insight into the developmental regulation of deiodinase expression has recently been obtained in the chicken growth plate, where Indian hedgehog induces WSB-1, an E3 ubiquitin ligase adaptor that inactivates D2 (7). The hedgehog pathway, acting through the Gli family of transcription factors, determines patterns of cell growth and differentiation in a wide variety of developmental settings (8)(9)(10)(11)(12)(13).…”

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confidence: 99%

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Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Dentice

Luongo

Huang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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149

139

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The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. Here we show that Shh, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human BCCs. We demonstrate that Gli-induced D3 reduces intracellular active thyroid hormone, thus resulting in increased cyclin D1 and keratinocyte proliferation. D3 knockdown caused a 5-fold reduction in the growth of BCC xenografts in nude mice. Shh-induced thyroid hormone degradation via D3 synergizes with the Shh-mediated reduction of the type 2 deiodinase, the thyroxine-activating enzyme, and both effects are reversed by cAMP. This previously unrecognized functional cross-talk between Shh/Gli2 and thyroid hormone in keratinocytes is a pathway by which Shh produces its proliferative effects and offers a potential therapeutic approach to BCC.basal cell carcinoma ͉ thyroxine ͉ differentiation ͉ cancer T hyroid hormone action is regulated by the activity of the deiodinases. Type 2 deiodinase (D2) activates the prohormone thyroxine (T4) by converting it to thyroid hormone (T3), whereas D3, by inactivating T3, terminates thyroid hormone action (1). All vertebrates express D2 and D3 that, in adults, contribute to plasma T3 and T4 homeostasis by their concerted actions with the hypothalamic-pituitary feedback axis. This homeostatic mechanism is possible because the Dio3 gene is transcriptionally stimulated by T3, whereas D2 is inhibited by two thyroid hormone-mediated effects, a transcriptional downregulation of Dio2 as well as protein inactivation by ubiquitination (for review, see ref.2). During development, preprogrammed changes in D2 and D3 expression are thought to regulate intracellular T3 concentrations essential to the normal development of the central nervous system, including the retina and the inner ear (3-6). However, the signals governing the changes in D2 and D3 expression during these complex processes are largely unknown.New insight into the developmental regulation of deiodinase expression has recently been obtained in the chicken growth plate, where Indian hedgehog induces WSB-1, an E3 ubiquitin ligase adaptor that inactivates D2 (7). The hedgehog pathway, acting through the Gli family of transcription factors, determines patterns of cell growth and differentiation in a wide variety of developmental settings (8-13). Given that, in general, signals regulating D2 expression affect D3 in a reciprocal fashion (2), we hypothesized that hedgehog proteins could up-regulate D3 while suppressing D2 expression. To explore this possibility, we turned to skin, a system in which Sonic hedgehog (Shh) is known to play dominant physiological as well as pathological roles (14). Both D2 and D3 are present in skin, a well recognized target of thyroid hormone...

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Section: Resultsmentioning

confidence: 80%

mentioning

confidence: 99%

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Dentice

Luongo

Huang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

149

139

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“…At the same time, D2 exhibits strong posttranslational regulation via ubiquitination and proteasomal degradation by different components of the endoplasmic reticulum (162)(163)(164)(165). Thus, mRNA levels do not necessarily reflect protein expression or enzyme activity (162,166,167). The Dio3 gene is intronless, and thus appropriate controls are required given that even minimal DNA contamination could affect the RT-qPCR results.…”

Section: T 4 ) (B)mentioning

confidence: 99%

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

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“…The WD40 domain of WSB-1 also determines substrate specificity for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2). WSB-1 increases D2 ubiquitination in vitro, with its induction by Hedgehog leading to decreased D2 levels in vivo and a corresponding effect on thyroid hormone activation (75).…”

Section: Wd40 and Socs Box Protein Substratesmentioning

confidence: 99%

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

2012

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SummaryThe suppressor of cytokine signalling (SOCS) box was first identified in the SH2-containing SOCS box family (cytokine-inducible SH2-containing protein, SOCS1-7) and is a 40-amino acid motif, which functions to recruit an E3 ubiquitin ligase complex consisting of the adapter proteins elongins B and C, Rbx2 and the scaffold protein Cullin5. The SOCS box is found in a diverse array of intracellular signalling molecules, many of which contain different protein interaction domains such as SPRY and WD40 domains, leucine and ankyrin repeats or other functional domains such as GTPases. In general, the SOCS box-containing proteins are thought to act as substrate-recognition modules to mediate the polyubiquitination and subsequent degradation of substrate proteins by the 26S proteasome.

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The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate

Cited by 203 publications

References 35 publications

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

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