Identification and characterization of several dietary alkaloids as weak inhibitors of hedgehog signaling. |
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Authors: | Robert J Lipinski Emelyne Dengler Mark Kiehn Richard E Peterson Wade Bushman |
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Affiliation: | Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI 53703, USA. |
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Abstract: | The Hedgehog (Hh) signaling pathway plays an integral role in the patterning and development of diverse structures in the vertebrate embryo. Aberrations in Hh signaling are associated with a range of developmental defects including failure of interhemispheric division of the embryonic forebrain as well as midline facial dysmorphia including cleft lip/palate and cyclopia, collectively termed holoprosencephaly (HPE). Postnatally, Hh signaling has been postulated to play a pivotal role in healing and repair processes and inappropriate Hh pathway activation has been implicated in several types of cancers. The Veratrum alkaloid cyclopamine is a potent inhibitor of Hh signaling and causes HPE-like defects in diverse species including sheep, hamster, mouse, and zebra fish. Using murine cell-based assays, we have determined that a number of dietary alkaloids similar in structure to cyclopamine also inhibit Hh signaling but with significantly lower potency. We found that these dietary compounds act additively through a mechanism similar to cyclopamine, downstream of Ptc1 and upstream of Gli1. Using an embryonic zebra fish developmental assay, we found that while cyclopamine exposure caused HPE-like defects, exposure to one of these dietary compounds, solanidine, did not. |
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