Proteasome inhibitors prevent cytochrome <i>c</i> release during apoptosis but not in excitotoxic death of cerebellar granule neurons

Bobba, Antonella; Canu, Nadia; Atlante, Anna; Petragallo, Vito A.; Calissano, Pietro; Marra, Ersilia

doi:10.1016/s0014-5793(02)02231-7

Cited by 27 publications

(39 citation statements)

References 22 publications

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“…In contrast, proteasome inhibition had no inhibitory effect on apoptosis induced via the CD95 pathway (Dallaporta et al, 2000). Similar protective effects of proteasome inhibitors were found in differentiated neuronal cells (Sadoul et al, 1996) and rat cerebellar neurons (Bobba et al, 2002;Canu et al, 2000) undergoing apoptosis in response to deprivation of nerve growth factor and potassium, respectively, but not in cells undergoing necrosis (Bobba et al, 2002).…”

Section: Cell Deathmentioning

confidence: 76%

The role of the ubiquitin/proteasome system in cellular responses to radiation

et al. 2003

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Section: Cell Deathmentioning

confidence: 76%

The role of the ubiquitin/proteasome system in cellular responses to radiation

et al. 2003

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“…Indeed, we observed that inhibiting proteasome for 8 h prevented cytochrome c release, activation of caspase 3 and nuclear condensation in KCl-deprived CGNs (Figure 2), in agreement with previous studies. 15 -17 This suggests that key pro-survival proteins have to be degraded by the proteasome for apoptosis to be initiated in neurons. In contrast, incubation for 17 h with the same proteasome inhibitors was sufficient to induce 50% death in CGNs, even in the presence of 25 mM KCl (Figure 1d).…”

Section: Resultsmentioning

confidence: 99%

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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Short-term proteasome inhibition has been shown to prevent neuronal apoptosis. However, the key pro-survival proteins that must be degraded for triggering neuronal death are mostly unknown. Here, we show that Mcl-1, an anti-apoptotic Bcl-2 family member, is degraded by the proteasome during neuronal apoptosis. Using primary cultures of cerebellar granule neurons deprived of serum and KCl, we found that ubiquitination and proteasomal degradation of Mcl-1 depended on its prior phosphorylation by GSK3, providing the first insight into post-translational regulation of Mcl-1 in neurons. In a previous study, we have reported that the E3 ubiquitin-ligase Trim17 is both necessary and sufficient for neuronal apoptosis. Here, we identified In the nervous system, apoptosis plays a critical role both during development and in neurodegenerative diseases. 1 In many neuronal types, apoptosis is triggered through the intrinsic pathway of caspase activation that involves the release of cytochrome c from mitochondria. The proteins of the Bcl-2 family, that comprises both anti-apoptotic (Bcl-2, Bcl-x L , Mcl-1y) and pro-apoptotic members (Bax, Bak, Bimy), play an essential role in the regulation of apoptosis by controlling the integrity of the outer mitochondrial membrane and the release of apoptogenic factors such as cytochrome c. 2 Amongst the anti-apoptotic proteins of the Bcl-2 family, Mcl-1 (Myeloid cell leukemia 1) is characterized by a short half-life. 3 Its rapid degradation by the proteasome has been shown to be required for initiation of the apoptotic cascade in several cell lines. [4][5][6][7] For a long time, little attention was paid to a potential role for Mcl-1 in the nervous system because initial studies did not detect it in neurons. However, Mcl-1 is expressed in cerebellar granule neurons (CGNs) in vivo, 8 and Mcl-1 expression has been associated with neuroprotection in the hippocampus. 9 More recently, elegant studies using different conditional Mcl-1 mouse mutants, showed that Mcl-1 is required for neuronal development, that loss of Mcl-1 sensitizes neurons to DNA damage-induced apoptosis and that Mcl-1 negatively regulates autophagy in starved neurons. 10,11 Therefore, Mcl-1 appears to play a crucial role in neuronal survival. Nevertheless, post-translational regulation of Mcl-1 has never been studied in neurons.In the present study, we report for the first time that Mcl-1 is degraded by the proteasome during neuronal apoptosis. We found that Mcl-1 degradation depended on its prior phosphorylation by glycogen synthase kinase 3 (GSK3), in primary cultures of CGNs deprived of serum and KCl. This phosphorylation of Mcl-1 favored its physical interaction with Trim17, a novel E3 ubiquitin-ligase involved in neuronal apoptosis. Moreover, our present data provide evidence that Trim17 contributes to the ubiquitination and the proteasomal degradation of Mcl-1 in neurons. As such, we define a novel molecular mechanism for regulation of Mcl-1 and initiation of apoptosis. ResultsMcl-1 is degraded by the proteasome during...

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“…Furthermore, injection of a proteasome inhibitor into the lateral ventricle of rats significantly decreased NF-kB activity and resulted in apoptotic neuronal death in various CNS areas, suggesting that proteasome inhibition induces apoptotic neuronal death (Taglialatela et al, 1998). Also, incubation of different types of neurons with proteasome inhibitors was shown to induce cell death (Keller and Markesbery, 2000;Qiu et al, 2000;Bobba et al, 2002;Ding et al, 2006). These results would further suggest that proteasome inhibition contributes to neuronal death in brain ischemia.…”

Section: Protective Effects Of Proteasome Modulators In Brain Ischemiamentioning

confidence: 87%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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Proteasome inhibitors prevent cytochrome c release during apoptosis but not in excitotoxic death of cerebellar granule neurons

Cited by 27 publications

References 22 publications

The role of the ubiquitin/proteasome system in cellular responses to radiation

The role of the ubiquitin/proteasome system in cellular responses to radiation

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

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