|ZFIN ID: ZDB-PUB-070907-17|
Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling
Lipinski, R.J., Dengler, E., Kiehn, M., Peterson, R.E., and Bushman, W.
|Source:||Toxicological sciences : an official journal of the Society of Toxicology 100(2): 456-463 (Journal)|
|Registered Authors:||Peterson, Richard E.|
|PubMed:||17728282 Full text @ Toxicol. Sci.|
Lipinski, R.J., Dengler, E., Kiehn, M., Peterson, R.E., and Bushman, W. (2007) Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling. Toxicological sciences : an official journal of the Society of Toxicology. 100(2):456-463.
ABSTRACTThe 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 zebrafish. 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 zebrafish 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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