Bcl-2 Phosphorylation and Proteasome-Dependent Degradation Induced by Paclitaxel Treatment: Consequences on Sensitivity of Isolated Mitochondria to Bid

Brichese, Laetitia; Barboule, Nadia; Heliez, Christophe; Valette, Annie

doi:10.1006/excr.2002.5563

Cited by 46 publications

(32 citation statements)

References 29 publications

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“…Finally, consistent with their findings, we found that Bim-EL phosphorylation was not regulated through the PI3K/AKT pathway. Interestingly, Bcl-2, which is the major target of Bim, is also regulated via the proteasome pathway (Dimmeler et al, 1999;Breitschopf et al, 2000;Brichese et al, 2002). Of note, phosphorylation of Bcl-2 at serine 87 by Erk1/2 protects Bcl-2 from degradation by the proteasome and contributes to increased cell survival (Breitschopf et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

et al. 2003

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Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

et al. 2003

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“…Proteolysis of mitochondrial proteins is regulated by multiple mechanisms (35,36). The ubiquitin/proteasome system regulates molecules such as Mcl-1, a member of the Bcl-2 family in mitochondria (37)(38)(39)(40), indicating the importance of the protease system in the regulation of levels of Bcl-2 family proteins. However, in our preliminary experiments, treatment with proteasome inhibitors did not change the decrease in Bcl-xL (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Control of Mitochondrial Outer Membrane Permeabilization and Bcl-xL Levels by Thioredoxin 2 in DT40 Cells

Wang

Masutani

Oka

et al. 2006

Journal of Biological Chemistry

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Mitochondria play a central role in the initiation of apoptosis, which is regulated by various factors such as ATP synthesis, reactive oxygen species, redox status, and outer membrane permeabilization. Disruption of chicken thioredoxin 2 (Trx2), a mitochondrial redox-regulating protein, results in apoptosis in DT40 cells. To investigate the mechanism of this apoptosis, we prepared transfectants expressing control (DT40-TRX2؊/؊), human thioredoxin 2 (TRX2) (DT40-hTRX2), or redox-inactive TRX2 (DT40-hTRX2CS) in conditional Trx2-deficient DT40 cells containing a tetracyclinerepressible Trx2 gene. Production of ATP was not significantly changed by down-regulation of Trx2 expression. The generation of reactive oxygen species was enhanced by the down-regulation of Trx2 expression in DT40-TRX2؊/؊. Unexpectedly, the change was blocked in both DT40-hTRX2 and DT40-hTRX2CS cells. The down-regulation of Trx2 expression caused the release of cytochrome c and apoptosis-inducing factor on day 3, and apoptosis on day 5. These changes were also suppressed in both DT40-hTRX2 and DT40-hTRX2CS cells, suggesting that TRX2 regulates mitochondrial outer membrane permeabilization and apoptosis by redox-active site cysteine-independent mechanisms. The downregulation of Trx2 expression caused a decrease in the protein level of Bcl-xL on day 3, whereas the protein level of Bcl-2 did not change until day 4, and the mRNA level of Bcl-xL was unchanged. The decrease in Bcl-xL was not blocked by a caspase 3 inhibitor but blocked in both DT40-hTRX2 and DT40-hTRX2CS. These findings indicate a link between the redox active site cysteine-independent action of TRX2 and the level of Bcl-xL in the regulation of apoptosis.

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“…For example, some cell lines expressing phospho-defective forms of Bcl-2 are more resistant to microtubule inhibitors, suggesting that phosphorylation disables Bcl-2 antiapoptotic function (Srivastava et al, 1999;Yamamoto et al, 1999). However, other reports suggest that drug-induced multisite phosphorylation may stabilize Bcl-2 and promote its antiapoptosis function (Brichese et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Characterization of vinblastine-induced Bcl-xL and Bcl-2 phosphorylation: evidence for a novel protein kinase and a coordinated phosphorylation/dephosphorylation cycle associated with apoptosis induction

Lyle

Chambers

2004

Oncogene

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Bcl-2 Phosphorylation and Proteasome-Dependent Degradation Induced by Paclitaxel Treatment: Consequences on Sensitivity of Isolated Mitochondria to Bid

Cited by 46 publications

References 29 publications

Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

Control of Mitochondrial Outer Membrane Permeabilization and Bcl-xL Levels by Thioredoxin 2 in DT40 Cells

Characterization of vinblastine-induced Bcl-xL and Bcl-2 phosphorylation: evidence for a novel protein kinase and a coordinated phosphorylation/dephosphorylation cycle associated with apoptosis induction

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