A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism.
In this work we present evidence that A769662, a novel activator of AMP-activated protein kinase (AMPK), is able to inhibit the function of the 26S proteasome by an AMPK-independent mechanism. Contrary to the mechanism of action of most proteasome inhibitors, A769662 does not affect the proteolytic activities of the 20S core subunit, defining in this way a novel mechanism of inhibition of 26S proteasome activity. Inhibition of proteasome activity by A769662 is reversible and leads to an arrest of cell cycle progression. These side effects of this new activator of AMPK should be taken into account when this compound is used as an alternative activator of the kinase.
Moreno
Daniel
D
Instituto de Biomedicina de Valencia, CSIC, Jaime Roig 11, Valencia, Spain.
Knecht
Erwin
E
Viollet
Benoit
B
Sanz
Pascual
P
D055372:AMP-Activated Protein Kinases; D001713:Biphenyl Compounds; D002460:Cell Line; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D001713:Biphenyl Compounds; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011753:Pyrones; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile