Novel pathway compendium analysis elucidates mechanism of pro-angiogenic synthetic small molecule.
Bioinformatics
; 24(20): 2384-90, 2008 Oct 15.
Article
in En
| MEDLINE
| ID: mdl-18718940
ABSTRACT
MOTIVATION Computational techniques have been applied to experimental datasets to identify drug mode-of-action. A shortcoming of existing approaches is the requirement of large reference databases of compound expression profiles. Here, we developed a new pathway-based compendium analysis that couples multi-timepoint, controlled microarray data for a single compound with systems-based network analysis to elucidate drug mechanism more efficiently. RESULTS:
We applied this approach to a transcriptional regulatory footprint of phthalimide neovascular factor 1 (PNF1)-a novel synthetic small molecule that exhibits significant in vitro endothelial potency-spanning 1-48 h post-supplementation in human micro-vascular endothelial cells (HMVEC) to comprehensively interrogate PNF1 effects. We concluded that PNF1 first induces tumor necrosis factor-alpha (TNF-alpha) signaling pathway function which in turn affects transforming growth factor-beta (TGF-beta) signaling. These results are consistent with our previous observations of PNF1-directed TGF-beta signaling at 24 h, including differential regulation of TGF-beta-induced matrix metalloproteinase 14 (MMP14/MT1-MMP) which is implicated in angiogenesis. Ultimately, we illustrate how our pathway-based compendium analysis more efficiently generates hypotheses for compound mechanism than existing techniques.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Gene Expression Profiling
/
Angiogenesis Inducing Agents
/
Indoles
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Bioinformatics
Journal subject:
INFORMATICA MEDICA
Year:
2008
Document type:
Article
Affiliation country:
United States