RT Journal Article
SR Electronic
T1 (2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 282
OP 288
DO 10.1124/mol.108.045690
VO 74
IS 1
A1 Marie-Claude Lauzier
A1 Geneviève A. Robitaille
A1 Denise A. Chan
A1 Amato J. Giaccia
A1 Darren E. Richard
YR 2008
UL http://molpharm.aspetjournals.org/content/74/1/282.abstract
AB Hypoxia-inducible factors (HIFs) are unstable heterodimeric transcription factors and decisive elements for the transcriptional regulation of genes important in the adaptation to low-oxygen conditions. Hypoxia is the ubiquitous inducer of HIFs, stabilizing the α-subunit and permitting the formation of a functional HIF complex. Here, we identify (2R)-[(4-biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a commercially available metalloprotease-2 and -9 inhibitor, as a rapid and potent inducer of HIFs. We show that in different cell lines, BiPS induces the HIF-α subunit by inhibiting its degradation through stabilization of its labile oxygen-dependent degradation domain. This is achieved through the inhibition of HIF-1α hydroxylation. The HIF-1 complex, formed after BiPS treatment, is capable of DNA binding and activation of HIF target genes, including the expression of vascular endothelial growth factor. Because novel HIF activators have generated considerable interest in the possible treatment of different ischemic diseases, we believe that BiPS and derivative molecules could have strong therapeutic potential. The American Society for Pharmacology and Experimental Therapeutics