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Linder, B.* ; Weber, S. ; Dittmann, K.H.* ; Adamski, J. ; Hahn, H.* ; Uhmann, A.*

A functional and putative physiological role of calcitriol in Patched1/Smoothened interaction.

J. Biol. Chem. 290, 19614-19628 (2015)
Verlagsversion DOI PMC
Open Access Gold
The Patched1 (Ptch)-mediated inhibition of Smoothened (Smo) is still an open question. However, a direct Ptch/Smo interaction has been excluded, Smo modulators were identified, but the endogenous signal transmitting molecule remains undiscovered. Here, we demonstrate that calcitriol, the hormonally active form of vitamin D3, is an excellent candidate for transmission of Ptch/Smo interaction. Our study reveals that Ptch expression is sufficient to release calcitriol from the cell and that calcitriol inhibits Smo action and ciliary translocation by acting on a site distinct from the 7-transmembrane-domain or the cysteine-rich-domain. Moreover calcitriol strongly synergizes with itraconazole (ITZ) in Smo inhibition which not results from elevated calcitriol bio-availability due to ITZ-mediated 24-hydroxylase inhibition but rather from a direct interaction of the compounds at the level of Smo. Together, we suggest that calcitriol represents a possible endogenous transmitter of Ptch/Smo interaction. Moreover calcitriol or calcitriol derivatives combined with ITZ might be a treatment option of Hedgehog-associated cancers.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hedgehog Signaling Pathway ; Cancer ; Cancer Therapy ; Cell Signaling ; Signal Transduction ; Vitamin D; Basal-cell Carcinoma; Sterol-sensing Domain; Sonic Hedgehog; Cholesterol Homeostasis; Signal-transduction; Vitamin-d; Proliferation; Pathway; Cyclopamine; Mutations
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 290, Heft: 32, Seiten: 19614-19628 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort Bethesda
Begutachtungsstatus Peer reviewed
Institut(e) Molekulare Endokrinologie und Metabolismus (MEM)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-505600-001
PubMed ID 26126827
DOI 10.1074/jbc.M115.646141
WOS ID WOS:000359364600023
Scopus ID 84939621422
Erfassungsdatum 2015-07-03
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