Caspase-3-derived C-terminal Product of Synphilin-1 Displays Antiapoptotic Function via Modulation of the p53-dependent Cell Death Pathway

Giaime, Emilie; Sunyach, Claire; Grosso, M.; Auberger, Patrick; McLean, Pamela J.; Checler, Frédéric; Costa, Cristine Alves da

doi:10.1074/jbc.m508619200

Cited by 35 publications

(28 citation statements)

References 65 publications

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“…The C-terminal fragment of synphilin-1, generated by caspase-dependent cleavage, is responsible for the anti-apoptotic function of synphilin-1. The uncleavable mutant form of synphilin-1 exhibits a markedly reduced anti-apoptotic activity (77). In the case of DJ-1, caspase 6-dependent cleavage generates a C-terminal fragment of DJ-1, which blocks the p53 pathway and inhibits apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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PP2A:B56ϵ, a Substrate of Caspase-3, Regulates p53-dependent and p53-independent Apoptosis during Development

Jin

Wallace

Harper

et al. 2010

Journal of Biological Chemistry

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Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine protein phosphatases. A large body of evidence suggests that PP2A is a tumor suppressor and plays critical roles in regulating apoptosis. PP2A is a heterotrimeric protein complex. Its substrate specificity, localization, and activity are regulated by regulatory subunits of PP2A. A recent study has demonstrated that single nucleotide polymorphism in B56⑀ (PPP2R5E), a B56 family regulatory subunit of PP2A, is associated with human soft tissue sarcoma. This raises the possibility that B56⑀ is involved in tumorigenesis and plays important roles in regulating apoptosis. However, this hypothesis has not been tested experimentally. Our previous studies revealed that B56⑀ regulates a number of developmental signaling pathways during early embryonic patterning. Here we report novel functions of B56⑀ in regulating apoptosis. We provide evidence that B56⑀ has both anti-and pro-apoptotic functions. B56⑀ suppresses p53-independent apoptosis during neural development, but triggers p53-dependent apoptosis. Mechanistically, B56⑀ regulates the p53-dependent apoptotic pathway solely through controlling the stability of p53 protein. In addition to its function in regulating apoptosis, we show that B56⑀ undergoes proteolytic cleavage. The cleavage of B56⑀ is mediated by caspase-3 and occurs on the carboxyl side of an evolutionarily conserved N-terminal "DKXD" motif. These results demonstrate that B56⑀, a substrate of caspase-3, is an essential regulator of apoptosis. So far, we have identified an alternative translation isoform and a caspase cleavage product of B56⑀. The significance of post-transcriptional regulation of B56⑀ is discussed.After decades of research since the discovery of protein phosphorylation, it is now appreciated that reversible protein phosphorylation is one of the major mechanisms for regulating cellular behavior. Reversible protein phosphorylation is executed by protein kinases and protein phosphatases. The human genome contains more than 500 protein kinase genes (1), but only a small number of protein phosphatases. Interestingly, many protein phosphatases are multimeric enzymes, with a few catalytic subunits being associated with many different regulatory subunits. This gives rise to sufficient numbers of protein phosphatases with different catalytic activity, substrate specificity, or intracellular localization to counteract the activities of protein kinases. Protein phosphatases 2A (PP2A) 2 is one of the most abundantly expressed Ser/Thr protein phosphatases. PP2A holoenzymes consist of a catalytic subunit (PP2Ac), a structural subunit (PP2Aa), and a regulatory subunit (B). Although PP2Ac exhibits fairly poor specificity in vitro, its activity in vivo is tightly regulated by multiple families of PP2A regulatory subunits, including B55/B, B56/BЈ, and PR72/BЉ. Investigation into individual regulatory subunits is central to understanding the mechanisms by which PP2A functions in a variety of cellular events (2-4).PP2A is a ...

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Section: Discussionmentioning

confidence: 99%

“…In 2006, Giaime et al (77) reported that synphilin-1, an anti-apoptotic protein that inhibits the expression of p53, is a substrate of caspase-3. The C-terminal fragment of synphilin-1, generated by caspase-dependent cleavage, is responsible for the anti-apoptotic function of synphilin-1.…”

Section: Discussionmentioning

confidence: 99%

PP2A:B56ϵ, a Substrate of Caspase-3, Regulates p53-dependent and p53-independent Apoptosis during Development

Jin

Wallace

Harper

et al. 2010

Journal of Biological Chemistry

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“…Indeed, there is evidence in cultured cells that caspase-3 mediates neuroprotection after preconditioning (30) and that caspase-3 activity turns on the antiapoptotic Akt kinase following partial cleavage of the RasGAP protein (47). Other caspase substrates that could potentially induce protective signals once cleaved include p27 kip1 (14), Lyn (28), synphilin-1 (19), and Rb (42), yet the physiological importance of these cleaved substrates has not been evaluated to date.…”

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confidence: 99%

Caspase-3 Protects Stressed Organs against Cell Death

Khalil

Peltzer

Walicki

et al. 2012

Molecular and Cellular Biology

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The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response. Executioner caspases mediate cell death during apoptosis (45). Of these, caspase-3 has the ability to cleave the majority of the caspase substrates (43), and its activity is required for the induction of cell death in response to many apoptotic stimuli (1). While executioner caspases are indispensable for apoptosis, there are situations when their activation does not lead to death. For example, healthy dividing cells can weakly activate caspase-3 in response to mild stresses (47). Caspase-3 also participates, in an apoptosisindependent manner, in T and B cell homeostasis (35,46), in microglia activation (6), in long-term depression (26), and in muscle (17), monocyte (44), embryonic stem cell (18), and erythroid cell (13) differentiation. However, it remains unclear how activation of caspase-3 under these conditions does not eventually lead to cell death (1, 24). Cells could have an intrinsic ability to tolerate low caspase activity by constitutively expressing antiapoptotic molecules, such as members of the inhibitors of the apoptosis protein family, or may stimulate antiapoptotic pathways in parallel to caspase activation (24). Alternatively, the caspases themselves might activate prosurvival pathways, in particular, when they are mildly stimulated. Indeed, there is evidence in cultured cells that caspase-3 mediates neuroprotection after preconditioning (30) and that caspase-3 activity turns on the antiapoptotic Akt kinase following partial cleavage of the RasGAP protein (47). Other caspase substrates that could potentially induce protective signals once cleaved include p27 kip1 (14), Lyn (28), synphilin-1 (19), and Rb (42), yet the physiological importance of these cleaved substrates has not been evaluated to date.In the present study, we have investigated the role played by caspase-3 and its substrate p120 RasGAP in the induction of the antiapoptotic Akt kinase in stressed tissues in vivo. MATERIALS AND METHODS Caspase-3-KO mice. B6.129S1...

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“…Their ages ranged from 39 to 70 and Eastern Cooperative Oncology Group (ECOG) performances ranged from 1-4 (Table 1 & 2). Patients were divided into 2 groups.…”

Section: Methodsmentioning

confidence: 99%

Can Nigella Sativa and Pure Honey Improved Chemoradiotherapy Effects in Advanced Pancreatic Cancer

Mayadağlı¹

2017

JNHFE

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Caspase-3-derived C-terminal Product of Synphilin-1 Displays Antiapoptotic Function via Modulation of the p53-dependent Cell Death Pathway

Cited by 35 publications

References 65 publications

PP2A:B56ϵ, a Substrate of Caspase-3, Regulates p53-dependent and p53-independent Apoptosis during Development

PP2A:B56ϵ, a Substrate of Caspase-3, Regulates p53-dependent and p53-independent Apoptosis during Development

Caspase-3 Protects Stressed Organs against Cell Death

Can Nigella Sativa and Pure Honey Improved Chemoradiotherapy Effects in Advanced Pancreatic Cancer

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