Cell chemical biology · 2017 · 57 citations · 37 references
MedicineCancer BiologyOncologyBiochemical PharmacologyCancer PharmacologyMolecular OncologyCell Cycle ControlCell Cycle PharmacologyCell Cycle SignalingCell-cycle DysregulationCell-cycle RegulationCyclin-dependent KinasesCell Cycle InhibitionCell Cycle InhibitorsCell Cycle-targeted TherapeuticsCyclin D RegulationCyclin DegradationCyclin RegulationP53 InactivationP53-mediated Cell-cycle Arrest
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types.
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NIH Image to ImageJ: 25 years of image analysis
Caroline A Schneider, Wayne Rasband, Kevin W. Eliceiri · Nature Methods · 2012 · 65.2K citations