Phosphorylation of the pro-apoptotic protein Bim in lymphocytes is associated with protection from apoptosis

Seward, Robert J.; Haller, Priska D. von; Aebersold, Ruedi; Huber, Brigitte

doi:10.1016/s0161-5890(03)00047-6

Cited by 42 publications

(48 citation statements)

References 29 publications

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“…Bim EL in band 2 was, however, relatively unaffected by alkaline phosphatase. This could be because the conformation of the protein makes some of the phosphorylation sites inaccessible for that phosphatase or that some other proteins are associated with Bim EL in agreement with observations by Seward et al (2003) on the same protein. Cells were also treated with an inhibitor of JNK, SP600125.…”

Section: Resultssupporting

confidence: 70%

Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

et al. 2005

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Components of garlic (Allium sativum) can cause disruption of microtubules, cell cycle arrest, and apoptosis in cancer cells. We show here that a water-soluble extract of garlic arrested MDA-MB-435 cancer cells in mitosis and caused apoptosis. The proapoptotic BH3-only, bcl-2 family protein Bim EL , which in healthy cells can be tightly sequestered to the microtubule-associated dynein motor complex, was modified after garlic treatment. The main effect of garlic on Bim EL was a considerable increase in a phosphorylated form of the protein. This phosphorylation(s), probably partly dependent on c-jun N-terminal kinase activity, promoted mitochondrial localisation of Bim EL . Furthermore, inhibition of extracellular signal-regulated kinases 1/2 increased the amount of another form of Bim EL present in the mitochondrial cellular fraction. Treatment of cells with the garlic compound diallyl disulphide had similar effects on Bim EL . The results indicate that the apoptotic effect of garlic and a combination of garlic and the inhibitor of extracellular signalregulated kinases 1/2 in MDA-MB-435 cells partly is due to modifications that are necessary for translocation of the proapoptotic protein Bim EL to mitochondria where it executes its proapoptotic function.

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Section: Resultssupporting

confidence: 70%

Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

et al. 2005

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“…This highlights the fact that these BaF3/Bcr-Abl cells are responsive to STI571 treatment and underscores the apoptotic function of Bim in Bcr-Abl signalling. Besides being regulated at transcriptional level by FoxOs, Bim has also been shown to be negatively controlled by phosphorylation (Biswas and Greene, 2002;Seward et al, 2003) and ubiquitination-mediated turnover (Akiyama et al, 2003;Ley et al, 2003Ley et al, , 2004Luciano et al, 2003). We have not determined in this study whether these post-translational mechanisms also contribute towards the apoptosis induced by STI571.…”

Section: Discussionmentioning

confidence: 85%

Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

et al. 2005

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In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Ablpositive BV173 and BaF3/Bcr-Abl cells. Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis. Using reporter gene assays, we demonstrate that STI571 and FoxO3a activate Bim transcription through a FoxO-binding site (FHRE) located within the promoter. This was verified by DNA pull-down and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to induction of Bim expression and apoptosis. Conversely, silencing of FoxO3a in Bcr-Abl-expressing cells abolishes STI571-mediated Bim induction and apoptosis. Together, the results presented clearly confirm FoxO3a as a key regulator of apoptosis induced by STI571, and show that Bim is a direct transcriptional target of FoxO3a that mediates the STI571-induced apoptosis. Thus, STI571 induces an accumulation of FoxO3a activity which in turn binds directly to an FHRE in the promoter to activate Bim expression and apoptosis.

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“…The BimEL isoform was converted to a shorter protein indicative of dephosphorylation, a modification previously shown to reduce its ability to bind Bax and prepare it for proteasomal degradation. 31,32 The presence of mitochondrially localized active Bax associated with p53, and finally cyt c release, all predicted an impending apoptotic caspase cascade. Despite early events indicative of a classical intrinsic apoptotic pathway, however, the proportion of Ann V-positive cells was low, death was largely caspaseindependent and the characteristic DNA fragmentation observed in apoptotic cells was absent (not shown).…”

Section: Discussionmentioning

confidence: 99%

Autophagy delays apoptotic death in breast cancer cells following DNA damage

et al. 2006

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Early signaling in camptothecin-treated MCF-7 cells followed an intrinsic pathway, but death was delayed and late events exhibited few hallmarks of apoptosis. BH3-only proteins, such as Noxa, Puma and BimEL, were activated and localized to mitochondrial sites within 24 h following drug exposure. However, caspase activity was low and death was unaffected by caspase inhibition. Transmission electron micrographs showed the presence of large vacuoles in drug-treated cells. An autophagic survival response has been attributed to MCF-7 cells following nutrient starvation or exposure to tamoxifen. Here, we show that autophagy also plays an important role in the delayed DNA damage response. Confocal microscopy revealed colocalization of mitochondria with large autophagic vacuoles and inhibitors of autophagy increased mitochondrial depolarization and caspase-9 activity, and accelerated cell death. Furthermore, downregulation of autophagy proteins, Beclin 1 and Atg7, unmasked a caspase-dependent, apoptotic response to DNA damage. We propose that a post-mitochondrial caspase cascade is delayed as a result of early disposal of damaged mitochondria within autophagosomes. Our data also suggest that the use of autophagy as a means of delaying apoptosis or prolonging survival may be characteristic of noninvasive breast tumor cells. These studies underscore a potential role for autophagy inhibitors in combination with conventional chemotherapeutic drugs in early breast cancer therapy.

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Phosphorylation of the pro-apoptotic protein Bim in lymphocytes is associated with protection from apoptosis

Cited by 42 publications

References 29 publications

Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

Autophagy delays apoptotic death in breast cancer cells following DNA damage

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