PUBLICATION
Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling
- Authors
- Lipinski, R.J., Dengler, E., Kiehn, M., Peterson, R.E., and Bushman, W.
- ID
- ZDB-PUB-070907-17
- Date
- 2007
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 100(2): 456-463 (Journal)
- Registered Authors
- Peterson, Richard E.
- Keywords
- none
- MeSH Terms
-
- Abnormalities, Drug-Induced
- Alkaloids/chemistry
- Alkaloids/toxicity*
- Animals
- Diet*
- Diosgenin/chemistry
- Diosgenin/toxicity
- Dose-Response Relationship, Drug
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/embryology
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Hedgehog Proteins/antagonists & inhibitors
- Hedgehog Proteins/drug effects*
- Mice
- Molecular Structure
- NIH 3T3 Cells
- Structure-Activity Relationship
- Transcription, Genetic/drug effects
- Veratrum Alkaloids/chemistry
- Veratrum Alkaloids/toxicity
- Zebrafish
- beta-Galactosidase/metabolism
- PubMed
- 17728282 Full text @ Toxicol. Sci.
Citation
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.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping