Four deaths and a funeral: from caspases to alternative mechanisms

Leist, Marcel; Jäättelä, Marja

doi:10.1038/35085008

Cited by 1,417 publications

(1,214 citation statements)

References 112 publications

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“…Since caspase activity is necessary for the classical characteristics of apoptosis, such as internucleosomal DNA fragmentation, 65 the deaths in the Apaf-1, caspase-9, -3 knockouts, and in the presence of zVAD-FMK are presumptively nonapoptotic or represent a variation of apoptosis. If so, we have demonstrated a correlation between Cdk5 activation and both classical apoptotic and nonapoptotic or nonclassical apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Lin

Zakeri

2005

Cell Death Differ

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Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclindependent kinase family that is mostly seen in neurons, does not vary with cell cycle, and is activated in many neurodegenerative disorders and other non-neuronal pathologies, but its relationship to non-neuronal apoptosis is not understood, nor is the control of the activation of Cdk5 by its activators. The most widely studied activator of Cdk5, p35, is cleaved to p25 by calpain, an event that has been linked with activation of Cdk5 and neuronal death. Here we report that calpain-mediated Cdk5/p25 activation accompanies nonneuronal as well as neuronal cell death, suggesting that the p35/calpain/p25/Cdk5 activation sequence is a general feature of cell death. We further demonstrate that Cdk5 can be activated in the absence of p53, Apaf-1, caspase-9, and -3 during cell death, indicating that its activation relates more to cell death than to a specific pathway of apoptosis.

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Section: Discussionmentioning

confidence: 99%

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Lin

Zakeri

2005

Cell Death Differ

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“…Surprisingly, block of the NHE induced caspase-independent apoptosis. Although initially disputed, several forms of caspase-independent apoptosis [33][34][35] or forms that are similar to apoptosis ('paraptosis') but also do not involve caspases have been reported. 30,36 Sperandio and colleagues (2000) characterized 'paraptosis' in 293T cells and mouse embryonic fibroblasts as a form of cell death without nuclear fragmentation and apoptotic bodies, but with cytoplasmic vacuolation and late mitochondrial swelling.…”

Section: Discussionmentioning

confidence: 99%

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

et al. 2004

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Potassium withdrawal is commonly used to induce caspasemediated apoptosis in cerebellar granule neurons in vitro. However, the underlying and cell death-initiating mechanisms are unknown. We firstly investigated potassium efflux through the outward delayed rectifier K þ current (I k ) as a potential mediator. However, tetraethylammoniumchloride, an inhibitor of I k , was ineffective to block apoptosis after potassium withdrawal. Since potassium withdrawal reduced intracellular pH (pH i ) from 7.4 to 7.2, we secondly investigated the effects of intracellular acidosis. To study intracellular acidosis in cerebellar granule neurons, we inhibited the Na þ /H þ exchanger (NHE) with 4-isopropyl-3-methylsulfonylbenzoylguanidine methanesulfonate (HOE 642) and 5-(N-ethyl-Nisopropyl)-amiloride. Both inhibitors concentration-dependently induced cell death and potentiated cell death after potassium withdrawal. Although inhibition of the NHE induced cell death with morphological criteria of apoptosis in light and electron microscopy including chromatin condensation, positive TUNEL staining and cell shrinkage, no internucleosomal DNA cleavage or activation of caspases was detected. In contrast to potassium withdrawal-induced apoptosis, cell death induced by intracellular acidification was not prevented by insulin-like growth factor-1, cyclo-adenosinemonophosphate, caspase inhibitors and transfection with an adenovirus expressing Bcl-X L . However, cycloheximide protected cerebellar granule neurons from death induced by potassium withdrawal as well as from death after treatment with HOE 642. Therefore, the molecular mechanisms leading to cell death after acidification appear to be different from the mechanisms after potassium withdrawal and resemble the biochemical but not the morphological characteristics of paraptosis.

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“…Mammalian cells can die from 'apoptosis' (showing nuclear condensation and fragmentation, DNA fragmentation and cytoplasmic condensation), 'necrosis' (generalized swelling of cells and organelles with limited or no chromatin condensation), and 'autophagic cell death' (death with accumulation of autophagosomes and subsequently vacuoles). Several intermediate or mixed cell death types have been reported, such as 'apoptosis-like' cell death with a less pronounced, subapoptotic chromatin condensation, 5 paraptosis, 6 oncosis, 3 necrapoptosis with cytoplasmic vacuolization and pronounced mitochondrial swelling not seen in apoptosis, 7 and apoptosis with autophagic vacuolization. 8,9 Importantly, different types of cell death can be induced in a context-dependent fashion by the very same initiating stimulus, for instance by binding of specific ligands to so-called death receptors anchored in the plasma membrane ( Figure 1).…”

Section: Cell Death Types Mechanisms and Stagesmentioning

confidence: 99%

Redundant cell death mechanisms as relics and backups

Golstein

Kroemer

2005

Cell Death Differ

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Here we review recent observations indicating the existence of redundant cell death mechanisms. We speculate that this redundancy reflects a particular evolutionary history for cellular demise. Autophagic or apoptotic elements might have been added to a primordial death mechanism, initially improving cell dismantling and later acquiring the ability to act themselves as death effectors. The resulting redundancy of cell death mechanisms has pathophysiological implications.

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Four deaths and a funeral: from caspases to alternative mechanisms

Cited by 1,417 publications

References 112 publications

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Redundant cell death mechanisms as relics and backups

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