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Interaction of the Hedgehog and vitamin D receptor signaling pathways in Patched associated cancers

dc.contributor.advisorHahn, Heidi Prof. Dr.
dc.contributor.authorLinder, Benedikt
dc.titleInteraction of the Hedgehog and vitamin D receptor signaling pathways in Patched associated cancersde
dc.contributor.refereeHahn, Heidi Prof. Dr.
dc.description.abstractengTumor formation can be linked to the misregulation of the developmentally important Hedgehog (Hh) signaling pathway. In general, Hh signaling is initiated by the secretion of Hh ligands. This is followed by the binding of Hh to the 12-pass transmembrane protein Patched (Ptch). Ptch normally represses the activity of the 7-pass transmembrane protein Smoothened (Smo). Binding of Hh to Ptch inhibits Ptch, thereby relieving the inhibition of Smo. Smo translocates into the primary cilium and mediates the activation of the members of the Glioma associated (Gli) family of transcription factors, leading to the transcription of target genes. The Smo protein harbors two domains important for its regulation by small-molecules, the seven-transmembraneous domain (7TM) and the N-terminal, extracellular cysteine-rich-domain (CRD). The mechanism by which Ptch inhibits Smo is not completely understood. A direct interaction of Ptch and Smo has been excluded and the inhibition is rather based on a catalytic mechanism involving small-molecule signal transmitters that are secreted in a Ptch-mediated manner. Indeed, recent data suggested that Ptch may secrete Smo inhibiting sterol-derivatives. Our recent data demonstrated that the secosteroid and hormonally active form of vitamin D3 (vitD3), calcitriol, inhibits Hh signaling at the level of Smo and reduces tumor growth in murine models for basal cell carcinoma (BCC) and rhabdomyosarcoma (RMS). In the present study we aimed to enhance the calcitriol-mediated antitumoral effects on BCC with antifungal azoles. Indeed, itraconazole (ITZ) but not the well-known Smo inhibitor cyclopamine (CP) strongly enhances calcitriol-mediated antitumoral response of the murine BCC cell line ASZ001. Furthermore, the combined effects of ITZ and calcitriol were not mediated by an enhanced bio-availability of calcitriol but by a synergistic inhibition of Hh signaling. Despite these promising in vitro data, no cooperative antitumoral effects of calcitriol and ITZ were achieved in two mouse models for BCC. Based on the findings that calcitriol inhibits Hh signaling at the level of Smo we next hypothesized that calcitriol is secreted by Ptch and investigated if calcitriol plays a key role in the physiological regulation of Hh signaling. Media transfer experiments and mass spectrometric analyses show that Ptch is indispensable for calcitriol release from the cells, but not for its synthesis. Second, generation of concentration-response curves, direct-competition assays and analyses of mutant Smo variants revealed that calcitriol does neither bind to the 7TM nor the CRD of Smo. This is in line with the current opinion that Ptch-mediated inhibition of Smo is unlikely to occur at the 7TM or the CRD. Taken together, our results indicate that calcitriol could be the first physiologically-existing Smo inhibitor to be
dc.contributor.coRefereeDobbelstein, Matthias Prof. Dr.
dc.subject.engvitamin dde
dc.subject.engmouse modelsde
dc.subject.engbasal cell carcinomade
dc.subject.engvitamin d receptorde
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de

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