Article

Human Caspases: Activation, Specificity, and Regulation

Program in Apoptosis and Cell Death Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2009; 284(33):21777-81. DOI: 10.1074/jbc.R800084200
Source: PubMed

ABSTRACT Caspases are intracellular proteases that propagate programmed cell death, proliferation, and inflammation. Activation of
caspases occurs by a conserved mechanism subject to strict cellular regulation. Once activated by a specific stimulus, caspases
execute limited proteolysis of downstream substrates to trigger a cascade of events that culminates in the desired biological
response. Much has been learned of the mechanisms that govern the activation and regulation of caspases, and this minireview
provides an update of these areas. We also delineate substantial gaps in knowledge of caspase function, which can be approached
by techniques and experimental paradigms that are currently undergoing development.

1 Follower
 · 
74 Views
  • Source
    • "Caspase-8 siRNA might protect normal cell proliferation and differentiation from Aβ1–40. Caspase activation was involved in apoptosis (Cohen, 1997; Ayala-Groeso et al. 2002; Amano et al. 2005; Denecker et al. 2008; Pop and Salvesen 2009; Hyman and Yuan 2012, 2012). The two classical apoptotic pathways are the intrinsic, or mitochondrial pathway, and the extrinsic pathway. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of Alzheimer’s disease (AD) is very complex and there are currently no significant treatments for the disease. Caspase-8 is known to be involved in neuronal apoptosis. To explore a possible molecular mechanisms involved in AD pathology, this study investigated the effect of caspase-8 knockdown on amyloid-β 1–40 (Aβ1–40)-induced apoptosis in PC12 cells. The proliferation of PC12 cells was significantly inhibited in Aβ-treated cells, and a high fraction of the cells underwent apoptosis in a dose- and time-dependent manner. Transfection of caspase-8 small interfering RNA (siRNA) resulted in reduced apoptosis following Aβ1–40 treatment. The activation of caspase-3, caspase-8, and caspase-9 was stimulated by Aβ1–40, an effect that was also significantly reduced by caspase-8 siRNA. Knockdown of caspase-8 increased the phosphorylation of the signaling molecules AKT and ERK1/2 relative to cells treated with Aβ1–40 alone. Caspase-8 is an important effector molecule involved in apoptosis induced by Aβ1–40 and is likely involved in AD pathology. This study suggests that targeted inhibition of caspase-8 may be a new therapeutic for preventing neuronal apoptosis and inhibiting the progression of AD.
    Journal of Molecular Neuroscience 02/2015; 56(2). DOI:10.1007/s12031-015-0498-5 · 2.76 Impact Factor
  • Source
    • "Active caspase - 9 next cleaves and activates the executioner caspases - 3 and - 7 . Ultimately , the executioner caspases cleave multiple protein substrates resulting in cell death ( Pop & Salvesen , 2009 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The classical view of mitochondria as housekeeping organelles acting in the background to simply maintain cellular energy demands has been shaken by mounting evidence of their direct and active participation in synaptic plasticity in neurons. Time-lapse imaging has revealed that mitochondria are motile in dendrites, with their localization and fusion and fission events regulated by synaptic activity. The positioning of mitochondria directly influences function of nearby synapses through multiple pathways including control over local concentrations of ATP, Ca+2, and reactive oxygen species. Recent studies have also shown that mitochondrial protein cascades classically associated with apoptosis are involved in neural plasticity in healthy cells. These findings link mitochondria to the plasticity- and metaplasticity-associated activity-dependent transcription factor MEF2 further repositioning mitochondria as potential command centers for regulation of synaptic plasticity. Intriguingly, MEF2 and mitochondrial functions appear to be intricately intertwined, as MEF2 is a target of mitochondrial apoptotic caspases and in turn, MEF2 regulates mitochondrial genome transcription essential for production of superoxidase and hydrogen peroxidase. Here, we review evidence supporting mitochondria as central organelles controlling the spatiotemporal expression of neuronal plasticity, and attempt to disentangle the MEF2-mitochondria relationship mediating these functions.This article is protected by copyright. All rights reserved
    The Journal of Physiology 12/2014; DOI:10.1113/jphysiol.2014.282459 · 4.54 Impact Factor
  • Source
    • "Caspases are fundamental executioners of apoptosis. They comprise a family of cysteine proteases which are synthesized as zymogens and are activated by proteolysis [6]. There are two main apoptotic pathways [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Flavonoids are polyphenolic compounds which display an array of biological activities and are considered potential antitumor agents. Here we evaluated the antiproliferative activity of selected synthetic flavonoids against human leukemia cell lines. We found that 4'-bromoflavonol (flavonol 3) was the most potent. This compound inhibited proliferation in a concentration-dependent manner, induced apoptosis and blocked cell cycle progression at the S phase. Cell death was found to be associated with the cleavage and activation of multiple caspases, the activation of the mitogen-activated protein kinase pathway and the up-regulation of two death receptors (death receptor 4 and death receptor 5) for tumor necrosis factor-related apoptosis-inducing ligand. Moreover, combined treatments using 4'-bromoflavonol and TRAIL led to an increased cytotoxicity compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.
    European Journal of Medicinal Chemistry 07/2014; 84C:30-41. DOI:10.1016/j.ejmech.2014.07.010 · 3.43 Impact Factor
Show more