PUBLICATION
A functional genomics approach to the mode of action of apratoxin A
- Authors
- Luesch, H., Chanda, S.K., Raya, R.M., Dejesus, P.D., Orth, A.P., Walker, J.R., Izpisúa Belmonte, J.C., and Schultz, P.G.
- ID
- ZDB-PUB-060216-7
- Date
- 2006
- Source
- Nature Chemical Biology 2(3): 158-167 (Journal)
- Registered Authors
- Izpisúa Belmonte, Juan Carlos
- Keywords
- none
- MeSH Terms
-
- Structure-Activity Relationship
- Fibroblast Growth Factors/antagonists & inhibitors
- Fibroblast Growth Factors/metabolism
- Tumor Cells, Cultured
- Apoptosis/drug effects
- Endothelial Cells/drug effects
- In Vitro Techniques
- STAT3 Transcription Factor/drug effects
- STAT3 Transcription Factor/metabolism
- Animals
- Humans
- Transcription, Genetic/drug effects
- Depsipeptides/pharmacology*
- Zebrafish/embryology
- Genomics/methods*
- Cell Cycle/drug effects*
- Cell Cycle/genetics
- Molecular Conformation
- Gene Expression Regulation/drug effects
- Signal Transduction/drug effects
- Signal Transduction/physiology
- Cell Proliferation/drug effects
- Phosphorylation
- RNA, Messenger/drug effects
- RNA, Messenger/genetics
- Drug Resistance, Neoplasm
- G1 Phase/drug effects
- PubMed
- 16474387 Full text @ Nat. Chem. Biol.
Citation
Luesch, H., Chanda, S.K., Raya, R.M., Dejesus, P.D., Orth, A.P., Walker, J.R., Izpisúa Belmonte, J.C., and Schultz, P.G. (2006) A functional genomics approach to the mode of action of apratoxin A. Nature Chemical Biology. 2(3):158-167.
Abstract
The cyanobacterial metabolite apratoxin A (1) demonstrates potent cytotoxicity against tumor cell lines by a hitherto unknown mechanism. We have used functional genomics to elucidate the molecular basis for this activity. Gene expression profiling and DNA content analysis showed that apratoxin A induces G1-phase cell cycle arrest and apoptosis. Cell-based functional assays with a genome-wide collection of expression cDNAs showed that ectopic induction of fibroblast growth factor receptor (FGFR) signaling attenuates the apoptotic activity of apratoxin A. This natural product inhibited phosphorylation and activation of STAT3, a downstream effector of FGFR signaling. It also caused defects in FGF-dependent processes during zebrafish development, with concomitant reductions in expression levels of the FGF target gene mkp3. We conclude that apratoxin A mediates its antiproliferative activity through the induction of G1 cell cycle arrest and an apoptotic cascade, which is at least partially initiated through antagonism of FGF signaling via STAT3.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping