A picture from our holiday lab lunch at La Taj.

Lab lunch Dec13

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Modulation of mitochondrial apoptosis in mitosis. (a) Central to mitochondrial apoptosis is the permeabilization of mitochondrial outer membrane by Bax and/or Bak multimers, leading to Cytochrome c release in the cytoplasm and subsequent activation of Caspase-9. This process is on one hand inhibited in mitosis by CDK1 (by direct phosphorylation of Caspase-2/8/9) and on the other hand promoted by inhibition of ‘Bax/Bak inhibitors’, that is, Bcl-2, Bcl-xL and Mcl-1. This latter phenomenon can occur either by direct inactivation of Bcl-2 and Bcl-xL by phosphorylation or by phosphorylation-dependent degradation of Mcl-1. Such degradation can have CDK1 and/or CKII/JNK/p38 as priming kinases and the APC/C-Cdc20 and/or SCF-FBW7 as phosphorylation-dependent Ubiquitin ligases, respectively. (b) Aurora A (and/or possibly Aurora B) kinase can reversibly phosphorylate Bim in mitosis and this modification is counteracted by the action of PP2A phosphatase. Phosphorylated Bim at Ser94/98 is selectively bound by SCF-βTrCP1, polyubiquitinated and degraded via the proteasome. Although the role of Bim in mitotic death remains to be fully understood, its regulation at the level of protein stability reveals how Aurora inhibitors might be used to promote cell death in mitosis.

The full editorial, published in Cell Death and Differentiation, can be found here: 

http://www.nature.com/cdd/journal/v20/n12/full/cdd2013140a.html

Published in the journal “Cell Death and Differentiation” and available online at:

http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd201393a.html
 
Abstract 
 
Bcl-2-interacting mediator of cell death (Bim) is a pro-apoptotic B-cell lymphoma 2 family member implicated in numerous apoptotic stimuli. In particular, Bim is required for cell death mediated by antimitotic agents, however, mitotic regulation of Bim remains poorly understood. Here, we show that the major splice variant of Bim, BimEL, is regulated during mitosis by the Aurora A kinase and protein phosphatase 2A (PP2A). We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. These findings describe a novel mechanism by which the oncogenic kinase Aurora A promotes cell survival during mitosis by downregulating proapoptotic signals. Notably, we observed that knockdown of Bim significantly increased resistance of cells to the Aurora A inhibitor MLN8054. Inhibitors of Aurora A are currently under investigation as cancer chemotherapeutics and our findings suggest that efficacy of this class of drugs may function in part by enhancing apoptotic activity of BimEL.

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Two abstracts were presented by the lab this year at the DNATV meeting in Birmingham, UK.  Thomas Kucharski presented a poster “Characterization of the Human Gyrovirus Type Interaction with the Anaphase-Promoting Complex” and Joe Teodoro presented an oral presentation entitled “Interaction of Adenovirus type 5 E4orf4 with the nucleoporin subunit Nup205 us required for proper viral gene expression”.

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Members of the Branton and Teodoro Lab got together at Mt St Hillaire to discuss some science and have some fun.

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