Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

Ley, Rebecca; Ewings, Katherine; Hadfield, Kathryn; Cook, Simon J.

doi:10.1038/sj.cdd.4401688

Cited by 285 publications

(351 citation statements)

References 47 publications

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“…Interestingly, mimicking microtubule stress by short hairpin(sh)RNA-mediated silencing of TACC3 expression completely failed to induce death of either cell line even after the prolonged absence of TACC3 for up to 6 days (Figures 1a-c). Consistent with these findings, TACC3 depletion, but not PTX treatment, was associated with reduced levels of Bim, a pro-apoptotic BH3-only protein that is activated by microtubule-disrupting agents and that links microtubule integrity to spindle poison-induced cell death (Ley et al, 2005). All three isoforms of Bim were downregulated in MCF-7 cells upon TACC3 depletion for 4-6 days ( Figure 1d), whereas the level of the anti-apoptotic protein Bcl-x L remained unaltered at these time points (data not shown).…”

Section: Resultssupporting

confidence: 68%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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Section: Resultssupporting

confidence: 68%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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“…This shift is consistent with the loss of a phosphorylation event on Bim-EL, and Bim-EL has previously been shown to be a target of ERK phosphorylation. [34][35][36] Therefore we assayed the phosphorylation of Bim-EL in IBC cells using a phospho-specific antibody. When ERK was inhibited by U0126 or PD0325901 treatment in KPL-4 or SUM149 cells, we observed a significant and dosedependent loss of Bim-EL phosphorylation at serine 59 (S59) (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

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“…15 The distinct isoforms differ in size and have different apoptotic activity owing to the presence or absence of specific exons (Figure 1a). 16 All three main splice variants contain the BH3 domain encoded by exon 8 that is required for binding to prosurvival proteins, and a predicted hydrophobic transmembrane (TM) region (exon 11). 15 Exon 4, present in both Bim L and Bim EL , but not in Bim S , encodes the dynein light chain (DLC)-binding motif required for interaction with DLC1.…”

Section: Resultsmentioning

confidence: 99%

Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets

et al. 2006

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All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short ahelical molecular recognition element can be considered to behave as a 'bead on a string'. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.

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Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

Cited by 285 publications

References 47 publications

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets

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