Calcium and apoptosis: facts and hypotheses

Meneghesso, Gaudenzio; Pinton, Paolo; Ferrari, Davide; Chami, Mounia; Szabadkai, György; Magalhães, Paulo; Virgilio, Francesco Di; Pozzan, Tullio

doi:10.1038/sj.onc.1207105

Cited by 437 publications

(328 citation statements)

References 91 publications

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“…Pro-and anti-apoptotic Bcl-2 proteins also localize to the ER 3,7 , and it is now recognized that the ER has an important role in regulating apoptosis 8,9 . The ER is thought to contribute to apoptosis through its role as the principle Ca 2+ storage organelle in cells [8][9][10][11] . At physiological levels, Ca 2+ released from the ER during…”

Section: Introductionmentioning

confidence: 99%

The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R

et al. 2005

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Members of the Bcl-2 protein family modulate outer mitochondrial membrane permeability to control apoptosis1 ,2 . However, these proteins also localize to the endoplasmic reticulum (ER), the functional significance of which is controversial 3, 4. Here we provide evidence that anti-apoptotic Bcl-2 proteins regulate the inositol 1,4,5-trisphosphate receptor (InsP 3 R) ER Ca 2+ release channel resulting in increased cellular apoptotic resistance and enhanced mitochondrial bioenergetics. Anti-apoptotic Bcl-X L interacts with the carboxyl terminus of the InsP 3 R and sensitizes single InsP 3 R channels in ER membranes to low [InsP 3 ], enhancing Ca 2+ and InsP 3 -dependent regulation of channel activity in vitro and in vivo, reducing ER Ca 2+ content and stimulating mitochondrial energetics. The proapoptotic proteins Bax and tBid antagonize this effect by blocking the biochemical interaction of Bcl-X L with the InsP 3 R. These data support a novel model in which Bcl-X L is a direct effector of the InsP 3 R, increasing its sensitivity to InsP 3 and enabling ER Ca 2+ release to be more sensitively coupled to extracellular signals. As a consequence, cells are protected against apoptosis by a more sensitive and dynamic coupling of ER to mitochondria through Ca 2+ -dependent signal transduction that enhances cellular bioenergetics and preserves survival.A central feature of molecular models of apoptosis is the control of outer mitochondrial membrane permeability by Bcl-2-related proteins. The pro-apoptotic Bcl-2-related proteins Bax and Bak are required to initiate cytochrome c release from mitochondria in response to diverse apoptotic stimuli 1,5 . Anti-apoptotic properties of Bcl-2 and Bcl-X L have been attributed to their ability to antagonize Bax/Bak by forming heterodimers that prevent their oligomerization and apoptosis initiation 6 . Pro-and anti-apoptotic Bcl-2 proteins also localize to the ER 3,7 , and it is now recognized that the ER has an important role in regulating apoptosis 8,9 . The ER is thought to contribute to apoptosis through its role as the principle Ca 2+ storage organelle in cells [8][9][10][11] . At physiological levels, Ca 2+ released from the ER during

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Section: Introductionmentioning

confidence: 99%

The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R

et al. 2005

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“…22,23,24 Both pathological increase of Ca 2 þ concentration in the cytosol compartment by inophores 25 and depletion of intracellular Ca 2 þ stores may trigger apoptosis by disrupting intracellular architecture and allowing effectors to gain access to their substrates. 24,26,27 Activation of apoptotic endonucleases 28 eliciting DNA cleavage and chromatin condensation has been well documented. 29,30,31 A tight buffering of intracellular Ca 2 þ is required for normal growth.…”

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confidence: 99%

“…29,30,31 A tight buffering of intracellular Ca 2 þ is required for normal growth. In fact, apoptosis can be induced by Ca 2 þ mobilization from intracellular pools, 23,24,27 chelation of intracellular Ca 2 þ with 1,2-bis-(2-aminophenoxy)ethane-N,N,N 1 ,N 1 -tetra-acetic acid tetra-acetoxymethyl ester (BAPTA-AM) 28,29 or removal of extracellular Ca 2 þ . 32 Intracellular Ca 2 þ deficiency regulates gene expression 22,26 and induces apoptosis through caspases activation.…”

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confidence: 99%

Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

et al. 2004

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Clusterin (CLU) is a secreted heterodimeric glycoprotein thatcan be produced almost ubiquitously in mammalians tissues.1Its gene expression is subjected to complex regulation and canchange enormously according to different stimuli.2 Cloned andidentified as the most potently induced gene in the regressingrat ventral prostate following androgen-ablation,3 CLU wasalmost simultaneously characterized and isolated by differentresearch groups working in widely divergent areas.2 CLU iscoded by a single copy gene, located on chromosome 8.4 Thegene codes for an initial precursor peptide glycosylated andcleaved into two a and b chains of 40 kDa each, held togetherby a unique five disulfide bond motif in the extracellular matureform.1 This secreted form of CLU has been suggested to act asa molecular chaperone following stress-induced injury,5clearing extracellular debris.6 However, it has been reportedthe existence of an inactive, cytoplasmic form of CLUproduced by alternative splicing that is converted by ionizingirradiation to a truncated mature nuclear isoform,7 which bindsthe Ku70/Ku80 complex in cell-free systems8 inhibiting cellgrowth and survival7 probably by a caspase-3-independentmechanism.9 Other alternative CLU isoforms, produced eitherby exon skipping10 or by post-translational modificationsactivated by apoptosis,11,12 were recently described. Thesedifferent isoforms of CLU have been suggested to beantiapoptotic6,13 or proapoptotic.7,10,12,14–16These controversial reports on the role of CLU might berelated to specific proteomic profiles that are produced bydifferent apoptotic stimuli (i.e. the general protein pattern ofCLU and the relative ratio between different CLU isoforms).This might explain why CLU has been involved in a plethora ofpathophysiological processes, including cell–cell and cell–matrix adhesion, cell differentiation, transformation, aging17,18and cancer,19 but its biological role still remains to be clearlyestablished. Reports suggesting that CLU may be a potentialtumor suppressor gene include the finding that CLU suppressesNF-kB activity and the metastatic phenotype ofneuroblastoma cells.20 We have previously reported that CLUoverexpression inhibits cell cycle progression of simian virus40(SV40)-immortalized human prostate PNT2 and PNT1Aepithelial cells.21To further assess the role of CLU in apoptotic processes wehave studied its expression pattern during the regulation ofcalcium homeostasis. Ca2þ is an important regulator ofapoptosis and cell survival.22,23,24 Both pathological increaseof Ca2þ concentration in the cytosol compartment byinophores25 and depletion of intracellular Ca2þ stores maytrigger apoptosis by disrupting intracellular architecture andallowing effectors to gain access to their substrates.24,26,27Activation of apoptotic endonucleases28 eliciting DNA cleavageand chromatin condensation has beenwell documented.29,30,31A tight buffering of intracellular Ca2þ is required for normalgrowth. In fact, apoptosis can be induced by Ca2þ mobilizationfrom intracellular pools,23,24,27 chelati...

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“…Additionally, Bcl-2 and related proteins are key components of the apoptotic process that modulate endoplasmic reticulum-associated Ca 2+ influx and maintain Ca 2+ homeostasis [7]. However, the mechanisms regulating the increase of intracellular Ca 2+ along with a role for Ca 2+ during apoptosis is not completely understood [8].…”

Section: Introductionmentioning

confidence: 99%

“…Activation of these endonucleases during apoptosis to digest chromosomal DNA and produce DNA fragmentation has been proposed as a mechanism for the propagation of apoptosis [17]. Therefore, it has been proposed that the increase in Ca 2+ concentration could be one of the triggers for the initiation of apoptosis [8], as well as being a late component of the process.…”

Section: Introductionmentioning

confidence: 99%

An endogenous calcium-dependent, caspase-independent intranuclear degradation pathway in thymocyte nuclei: Antagonism by physiological concentrations of K+ ions

Ajiro

Bortner

Westmoreland

et al. 2008

Experimental Cell Research

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Calcium ions have been implicated in apoptosis for many years, however the precise role of this ion in the cell death process remains incomplete. We have extensively examined the role of Ca 2+ on nuclear degradation in vitro using highly purified nuclei isolated from non-apoptotic rat thymocytes. We show that these nuclei are devoid of CAD (caspase-activated DNase), and DNA degradation occurs independent of caspase activity. Serine proteases rather than caspase-3 appear necessary for this Ca 2+ -dependent DNA degradation in nuclei. We analyzed nuclei treated with various concentrations of Ca 2+ in the presence of both a physiological (140 mM) and apoptotic (40 mM) concentration of KCl. Our results show that a 5-fold increase in Ca 2+ is required to induce DNA degradation at the physiological KCl concentration compared to the lower, apoptotic concentration of the cation. Ca 2+ -induced internucleosomal DNA degradation was also accompanied by the release of histones, however the apoptotic-specific phosphorylation of histone H2B does not occur in these isolated nuclei. Interestingly, physiological concentrations of K + inhibit both Ca 2+ -dependent DNA degradation and histone release suggesting a reduction of intracellular K + is necessary for this apoptosis-associated nuclear degradation in cells. Together, these data define an inherent caspaseindependent catabolic pathway in thymocyte nuclei that is sensitive to physiological concentrations of interacellular cations.

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Calcium and apoptosis: facts and hypotheses

Cited by 437 publications

References 91 publications

The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R

The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R

Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

An endogenous calcium-dependent, caspase-independent intranuclear degradation pathway in thymocyte nuclei: Antagonism by physiological concentrations of K+ ions

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