期刊
CHEMISTRY & BIOLOGY
卷 18, 期 2, 页码 252-263出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2010.12.008
关键词
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资金
- NSF [IOB 0642012, CHE 0846756]
- NIH [RO1 DK085300-01A1]
- NCSU CCMTR
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0846756] Funding Source: National Science Foundation
Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-beta-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indirectly inhibit the phosphorylation of an intracellular mediator of TGF-beta signaling. This combined phenotypic profile identifies these compounds as a class of TGF-beta signaling inhibitors. Notably, heterotaxin analogs also possess highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems. Our results suggest that assessing multiple organ, tissue, cellular, and molecular parameters in a whole organism context is a valuable strategy for identifying the mechanism of action of bioactive compounds.
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