Ca2+ -induced apoptosis through calcineurin dephosphorylation of BAD. Science
ABSTRACT The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.
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- "rphological rearrangements occurring concurrently with functional plasticity may be a consequence of caspase cleavage of cytoskeleton - associated proteins , including Gas2 , gelsolin , ROCK1 , β - catenin , fodrin , actin , PAK - 2 , spectrin and tau ( Brancolini et al . 1995 ; Cryns et al . 1996 ; Kothakota et al . 1997 ; Rudel & Bokoch , 1997 ; Wang et al . 1999 ; Gamblin et al . 2003 ; Williams et al . 2006 ) . Figure 2"
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 reservedThe Journal of Physiology 12/2014; 593(16). DOI:10.1113/jphysiol.2014.282459 · 5.04 Impact Factor
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- "Ang II activates calcium-calmodulin-dependent protein phosphatase calcineurin through Galphaq (Gα-q)/PLC signaling transduction [27, 30]. Ca2+/calcineurin also dephosphorylates pro-apoptotic Bcl-2 family protein Bad and induces cytochrome c release from mitochondria to the cytosol, which further induces caspase activation and cardiac cell apoptosis [27, 31]. We showed that Ang II stimulation causes apoptosis and induces caspase-9 and caspase-3 activation (Figure 4). "
ABSTRACT: Danggui (Radix Angelicae Sinensis) is an herb often used in Traditional Chinese medicine. It is used to promote blood flow and has been used in the treatment of myocardial ischemia-reperfusion injury in animal models. Angiotensin II (Ang II) has been shown to play important roles in mediating cardiovascular diseases, and may cause cardiac hypertrophy and apoptosis. This study aimed to investigate whether Danggui has protective effects on Ang II-induced apoptosis in H9c2 cardiomyoblast cells and study the mechanisms involved. We evaluated the effect of Danggui on Ang II-induced apoptosis in an in vitro model. H9c2 cardiomyoblast cells were cultured in serum-free medium for 4 hr, then treated with Danggui (50, 100 μg/ml) 1 hr pre- or post-Ang II treatment. After a further 23 hr of culture, cells were harvested for analyses with assays for apoptosis markers and cell signaling pathways. Our results showed that Ang II induced upregulation of pro-apoptotic Bad, instability of the mitochondria membrane potential, cytochrome c release, caspase-9 and caspase-3 activation and cardiomyocyte apoptosis. Pre- or post-treatment with Danggui reversed all of the above Ang II-induced apoptotic effects in H9c2 cells. Furthermore, the JNK (SP600125) inhibitor completely blocked Danggui inhibition of caspase-3 activation in Ang II-treated H9c2 cells. Our results showed that Danggui either pre-treatment or post-treatment highly attenuated the Ang II-induced apoptosis in cardiomyoblast cells. The findings demonstrated that the anti-apoptosis effect of Danggui is mediated by JNK and PI3k inhibitors.BMC Complementary and Alternative Medicine 09/2014; 14(1):358. DOI:10.1186/1472-6882-14-358 · 2.02 Impact Factor
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- "One of the important targets of AKT is a BCL-2 protein family member , BAD whose function is modulated by its phosphorylation at Ser112 and Ser136 residues (Gajewski and Thompson, 1996; Wang et al., 1996; Zha et al., 1996). In the absence of phosphorylation, BAD interacts with BCL-X L and suppresses cell survival by BAX homodimer formation (Wang et al., 1999). Conversely, BAD inactivation through its phosphorylation leads to its binding to 14-3-3 protein, a molecular chaperone (Muslin et al., 1996; Yaffe et al., 1997). "
ABSTRACT: The heme-regulated inhibitor (HRI), a regulator of translation initiation, is known to be activated and upregulated, and it acts as either a cytoprotective player promoting cell survival or as an inducer of apoptosis during stress. However, the exact role of HRI in these two responses has not been elucidated. In the present investigation, using human cell lines, we attempted to unravel the molecular mechanism(s) of HRI-mediated differential response and the involved signalling pathways. While during low dose (5μM) lead acetate treatment, cells did not show any diminished cell survival, significant level of apoptosis was observed at high dose (100μM) lead acetate. Based on the results of an interactome analysis, we determined the interaction of HRI with PI-3-Kca, only at a low dose stress, which is followed by phosphorylation and activation of its downstream target, AKT. Interestingly, such an interaction and AKT activation was not observed at a high dose stress. On the other hand, an increased level of APAF-1 and activation of caspases were observed. These results indicate a critical role of HRI in cell survival during low dose stress, and in apoptosis at high dose stress. Furthermore, HRI knockdown cells are sensitized even to 5μM lead treatment leading to caspase activation and apoptosis. Our results taken together thus elucidate for the first time the molecular mechanism and the involved signalling pathways for dose-dependent differential response of mammalian cells to lead exposure. These findings thus suggest the possibility of using HRI downregulation as a therapeutic strategy to sensitize cancer cells subjected to apoptogenic drugs.The International Journal of Biochemistry & Cell Biology 07/2014; 54. DOI:10.1016/j.biocel.2014.07.016 · 4.05 Impact Factor