Regulation of neutrophil apoptosis by Mcl-1

Edwards, Steven W.; Derouet, Mathieu; Howse, Matthew; Moots, Robert J.

doi:10.1042/bst0320489

Cited by 93 publications

(105 citation statements)

References 37 publications

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“…Mcl-1 is extensively regulated and has been associated with various signalling systems including PI3K, MAPK and glycogen synthase kinase [21,35]. It can be down-regulated at the level of transcription, translation and even degradation [17]. Mcl-1 may be degraded in the proteasome following phosphorylation and ubiquitination or may be disposed of in a caspasedependent manner [17][18][19][20].…”

Section: Discussionmentioning

confidence: 99%

“…It can be down-regulated at the level of transcription, translation and even degradation [17]. Mcl-1 may be degraded in the proteasome following phosphorylation and ubiquitination or may be disposed of in a caspasedependent manner [17][18][19][20]. It is also possible that a splice variant of Mcl-1 has pro-apoptotic capability, which may perhaps explain the rapid apoptosis that can accompany Mcl-1 downregulation.…”

Section: Discussionmentioning

confidence: 99%

“…Mcl-1 is a Bcl-2 homologue that promotes neutrophil survival by maintenance of the outer mitochondrial membrane against proapoptotic Bcl-2 family members. It is a rapidly transcribed, shortlived protein that is subject to prompt turnover by the proteasome [17]. Mcl-1 transcription and stability can be influenced by various signalling pathways (PI3K, ERK, glycogen synthase kinase, RAF), cytokines (GM-CSF, TNF-a) and pharmacological agents (dexamethasone, sodium salicylate) [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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Successful resolution of inflammation requires inflammatory cells such as neutrophils to undergo apoptosis prior to non-inflammatory phagocytosis by professional phagocytes. Recently, cyclin-dependent kinase (CDK) inhibitors (e.g. R-roscovitine) have been shown to induce neutrophil apoptosis and enhance the resolution of inflammation. Interestingly, NF-jB and MAPK pathways and key endogenous survival proteins (typified by Mcl-1) are involved in the regulation of neutrophil apoptosis and, in cancer-cell lines, have been implicated as possible targets of CDK inhibitors. Here, we demonstrate that R-roscovitine over-rides TNF-a and LPS-induced survival (determined by morphological examination and binding of fluorescently labelled annexin-V) of isolated peripheral blood neutrophils. This effect did not appear to be mediated via effects on early markers of neutrophil activation (e.g. surface marker expression, shape change, aggregation and superoxide anion generation), by direct inhibition of NF-jB activation (assessed by cytoplasmic IjBa proteolysis and NF-jB p65 subunit translocation) and ERK activation (determined by specific ERK phosphorylation) but due to down-regulation (at protein and mRNA level) of the survival protein Mcl-1 but not the pro-apoptotic bcl-2 homologue Bim. These findings suggest that key endogenous survival proteins may be the targets of CDK inhibitors and consequently may be of critical importance in the resolution of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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“…This is an important finding as eosinophils play a central role in the pathophysiology of common allergic diseases such as asthma and hay-fever as well as uncommon diseases such as eosinophilic oesophagitis, eosinophilic pneumonia and Churg-Strauss syndrome [1,10,35]. Eosinophils are also notoriously difficult to study for a number of reasons: their paucity in the peripheral blood of normal, healthy volunteer blood donors, the laborious isolation techniques required to ensure a pure population and their relative intractability to standard molecular biological techniques such as siRNA.…”

Section: Discussionmentioning

confidence: 99%

The CDK inhibitor, R‐roscovitine, promotes eosinophil apoptosis by down‐regulation of Mcl‐1

Duffin¹,

Leitch²,

Sheldrake³

et al. 2009

FEBS Letters

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a b s t r a c tEosinophils are major players in inflammatory allergic diseases such as asthma, hay fever and eczema. Here we show that the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine efficiently and rapidly induces human eosinophil apoptosis using flow cytometric analysis of annexin-V/propidium iodide staining, morphological analysis by light microscopy, transmission electron microscopy and Western immunoblotting for caspase-3 cleavage. We further dissect these observations by demonstrating that eosinophils treated with R-roscovitine lose mitochondrial membrane potential and the key survival protein Mcl-1 is down-regulated. This novel finding of efficacious induction of eosinophil apoptosis by CDKi drugs has potential as a strategy for driving resolution of eosinophilic inflammation.

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“…18 It is also required for the survival of haematopoietic stem cells 55 and myeloid cells. 56 The expression of Mcl-1 can be upregulated by a number of cytokines, including granulocyte-macrophage colony-stimulating factor, stem cell factor and interleukin (IL)-3, IL-5, IL-6, IL-7 and IL-15 in various haematopoietic cells. In addition, Mcl-1 is subject to post-translational modification.…”

Section: Activation Of Bh3-only Proteinsmentioning

confidence: 99%