title: Turning on caspases with genetics and small molecules.
abstract: Caspases, aspartate-specific cysteine proteases, have fate-determining roles in many cellular processes including apoptosis, differentiation, neuronal remodeling, and inflammation (for review, see Yuan & Kroemer, 2010). There are a dozen caspases in humans alone, yet their individual contributions toward these phenotypes are not well understood. Thus, there has been considerable interest in activating individual caspases or using their activity to drive these processes in cells and animals. We envision that such experimental control of caspase activity can not only afford novel insights into fundamental biological problems but may also enable new models for disease and suggest possible routes to therapeutic intervention. In particular, localized, genetic, and small-molecule-controlled caspase activation has the potential to target the desired cell type in a tissue. Suppression of caspase activation is one of the hallmarks of cancer and thus there has been significant enthusiasm for generating selective small-molecule activators that could bypass upstream mutational events that prevent apoptosis. Here, we provide a practical guide that investigators have devised, using genetics or small molecules, to activate specific caspases in cells or animals. Additionally, we show genetically controlled activation of an executioner caspase to target the function of a defined group of neurons in the adult mammalian brain.
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA; Graduate Group in Chemistry and Chemical Biology, University of California, San Francisco, California, USA.
authors: Charles W
authors: CW
authors: Morgan
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
authors: Olivier
authors: O
authors: Julien
authors: Department of Anatomy, University of California, San Francisco, California, USA; Program in Biomedical Sciences, University of California, San Francisco, California, USA.
authors: Elizabeth K
authors: EK
authors: Unger
authors: Department of Anatomy, University of California, San Francisco, California, USA. Electronic address: nms@ucsf.edu.
authors: Nirao M
authors: NM
authors: Shah
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA. Electronic address: jim.wells@ucsf.edu.
authors: James A
authors: JA
authors: Wells
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D060846:Cell Engineering / Q000379:methods; D003001:Cloning, Molecular / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D020169:Caspases
keywords: Activation; Aggression; Apoptosis; Caspase; Cell death; Cre-Lox; Protease; SNIPer; Sexual Behavior; VMHvl; Ventromedial Hypothalamus