Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes
- 4 September 2007
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (36), 14466-14471
- https://doi.org/10.1073/pnas.0706754104
Abstract
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.Keywords
This publication has 40 references indexed in Scilit:
- Deiodinases: implications of the local control of thyroid hormone actionJCI Insight, 2006
- Modelling cancer in human skin tissueNature Reviews Cancer, 2006
- The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plateNature, 2005
- Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesisHuman Molecular Genetics, 2004
- Transcription Factor Nkx-2.5 Induces Sodium/Iodide Symporter Gene Expression and Participates in Retinoic Acid- and Lactation-Induced Transcription in Mammary CellsMolecular and Cellular Biology, 2004
- Expression of Hypothalamic–Pituitary–Thyroid Axis RelatedGenes in the Human SkinJournal of Investigative Dermatology, 2002
- Inhibition of Hedgehog signaling by direct binding of cyclopamine to SmoothenedGenes & Development, 2002
- Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine SelenodeiodinasesEndocrine Reviews, 2002
- Sonic hedgehog signaling is essential for hair developmentCurrent Biology, 1998
- Thyroxine 5-deiodinase in human brain tumorsJournal of Clinical Endocrinology & Metabolism, 1993