Neuronal caspase-3 signaling: not only cell death

D’Amelio, Marcello; Cavallucci, Virve; Cecconi, Francesco

doi:10.1038/cdd.2009.180

Cited by 402 publications

(309 citation statements)

References 90 publications

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“…16 To confirm the extent of the toxic effects of MKP-1 in our system, we extended the analysis in dox-naive stables, surveying additional apoptotic signaling intermediates both proximate and distal to caspase-3 cleavage. Interestingly, basal MKP-1 expression in dox-naive stables was sufficient to induce cell death markers under control conditions mimicking the hypoxic phenotype in control cells.…”

Section: Resultsmentioning

confidence: 99%

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

et al. 2012

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The dual specificity phosphatase MAPK phosphatase-1 (MKP-1) feeds back on MAP kinase signaling to regulate metabolic, inflammatory and survival responses. MKP-1 is widely expressed in the central nervous system (CNS) and induced after ischemic stress, although its function in these contexts remains unclear. Here we report that MKP-1 activated several cell death factors, including BCL2 and adenovirus E1B 19 kDa interacting protein 3, and caspases 3 and 12 culminating in apoptotic cell death in vitro. MKP-1 also exerted inhibitory effects on the bZIP transcription factor CCAAT/enhancer-binding protein (C/EBPb), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBPb variant and hypo-phosphorylation at the MEK-ERK1/2-sensitive Thr 188 site. Notably, enforced expression C/EBPb rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBPb from the nucleus basally, and that MKP-1 antagonizes C/EBPb expression after global forebrain ischemia, particularly within the vulnerable CA1 sector of the hippocampus. Overall, MKP-1 appears to lower the cellular apoptotic threshold by inhibiting C/EBPb and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBPb axis could have therapeutic value in ischemic disorders, our observations using MKP-1 catalytic mutants suggest that approaches geared towards inhibiting MKP-1's phosphatase activity alone may be ineffective.

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Section: Resultsmentioning

confidence: 99%

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

et al. 2012

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“…1E), suggesting this as a possible mechanism behind its antiapoptotic role. Also, several studies have implicated caspase3 in nonapoptotic roles in neural development, including promotion of neurogenesis, refinement of neural circuits and synaptic plasticity [46][47][48][49]. Thus we cannot rule out the possibility that LIF, via reduced caspase3, could have affected other aspects of NP cell in vitro differentiation as well.…”

Section: Reduced Apoptosis Correlated To Reduction In Caspases and Rosmentioning

confidence: 94%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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Various growth factor cocktails have been used to proliferate and then differentiate human neural progenitor (NP) cells derived from embryonic stem cells (ESC) for in vitro and in vivo studies. However, the cytokine leukemia inhibitory factor (LIF) has been largely overlooked. Here, we demonstrate that LIF significantly enhanced in vitro survival and promoted differentiation of human ESC-derived NP cells. In NP cells, as well as NP-derived neurons, LIF reduced caspase-mediated apoptosis and reduced both spontaneous and H 2 O 2 -induced reactive oxygen species in culture. In vitro, NP cell proliferation and the yield of differentiated neurons were significantly higher in the presence of LIF. In NP cells, LIF enhanced cMyc phosphorylation, commonly associated with self-renewal/proliferation. Also, in differentiating NP cells LIF activated the phosphoinositide 3-kinase and signal transducer and activator of transcription 3 pathways, associated with cell survival and reduced apoptosis. When differentiated in LIF 1 media, neurite outgrowth and ERK1/2 phosphorylation were potentiated together with increased expression of gp130, a component of the LIF receptor complex. NP cells, pretreated in vitro with LIF, were effective in reducing infarct volume in a model of focal ischemic stroke but LIF did not lead to significantly improved initial NP cell survival over nontreated NP cells. Our results show that LIF signaling significantly promotes human NP cell proliferation, survival, and differentiation in vitro. Activated LIF signaling should be considered in cell culture expansion systems for future human NP cell-based therapeutic transplant studies.

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“…Upon the induction of apoptosis, procaspase-3 is proteolytically activated, and activated caspase-3 then executes many of the hallmark events of apoptosis (4,8). Hence, procaspase-3 activation is generally considered as an event associated with apoptotic cell death.…”

mentioning

confidence: 99%

Active Caspase-3 Is Stored within Secretory Compartments of Viable Mast Cells

Garcia-Faroldi

Melo

Rönnberg

et al. 2013

The Journal of Immunology

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Caspase-3 is a main executioner of apoptotic cell death. The general notion is that, in viable cells, caspase-3 is found as a cytosolic inactive proenzyme and that caspase-3 activation is largely confined to processes associated with cell death. In this study, we challenge this notion by showing that enzymatically active caspase-3 is stored in viable mast cells. The enzymatically active caspase-3 was undetectable in the cytosol of viable cells, but was recovered in subcellular fractions containing secretory granule-localized proteases. Moreover, active caspase-3 was rapidly released into the cytosolic compartment after permeabilization of the secretory granules. Using a cell-permeable substrate for caspase-3, the presence of active caspase-3–like activity in granule-like compartments close to the plasma membrane was demonstrated. Moreover, it was shown that mast cell activation caused release of the caspase-3 to the cell exterior. During the course of mast cell differentiation from bone marrow cells, procaspase-3 was present in cells of all stages of maturation. In contrast, active caspase-3 was undetectable in bone marrow precursor cells, but increased progressively during the process of mast cell maturation, its accumulation coinciding with that of a mast cell–specific secretory granule marker, mouse mast cell protease 6. Together, the current study suggests that active caspase-3 can be stored within secretory compartments of viable mast cells.

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Neuronal caspase-3 signaling: not only cell death

Cited by 402 publications

References 90 publications

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

Active Caspase-3 Is Stored within Secretory Compartments of Viable Mast Cells

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