MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on December 7, 2007; DOI: 10.1124/mol.107.042606

0026-895X/08/7303-919-929$20.00
Mol Pharmacol 73:919-929, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.042606v1
73/3/919    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nair, R. R.
Right arrow Articles by Yan, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nair, R. R.
Right arrow Articles by Yan, C.

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

Rajesh R. Nair, Hector Avila, Xujun Ma, Zhengxin Wang, Michelle Lennartz, Bryant G. Darnay, Douglas D. Boyd, and Chunhong Yan

Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York (X.M., M.L., C.Y.); and Department of Cancer Biology (R.R.N., H.A., Z.W., D.D.B.) and Experimental Therapeutics (B.G.D.), the University of Texas M.D. Anderson Cancer Center, Houston, Texas

Aberrant gene expression is one of the driving forces for cancer progression and is considered an ideal target for chemical intervention. Although emerging bioluminescence reporter systems allow high-throughput searches for small molecules regulatory for gene expression, frequent silencing of reporter genes by epigenetic mechanisms hinders wide application of this drug discovery strategy. Here we report a novel system that directs the integration of a promoter-reporter construct to an open chromosomal location by Flp-mediated homologous recombination, thereby overcoming reporter-gene silencing. Using this system, we have screened more than 8000 compounds in the DIVERSet chemical library for repressors of a matrix metalloproteinase-9 (MMP-9) promoter and identified 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) inhibitory for MMP-9 gene expression. Consistent with this effect, MPBD inhibits MMP-9-dependent invasion of UMSCC-1 oral cancer cells, preosteoclast migration, and receptor activator of nuclear factor-{kappa}B ligand-induced osteoclast activity over concentration ranges that repressed MMP-9 expression. Mechanistic studies indicated that MPBD antagonizes AP-1 function by inhibiting its transactivation activity. We conclude that the Flp-mediated homologous recombination system to direct reporter integration into open chromatin regions represents a novel strategy allowing for the development of high-throughput systems screening for lead compounds targeting aberrant gene expression in cancer.

Received October 10, 2007; accepted December 7, 2007

Address correspondence to: Dr. Chunhong Yan, Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208. E-mail: yanc{at}mail.amc.edu






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics