BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

Moustafa-Kamal, Mohamed; Gamache, Isabelle; Lü, Yu; Li, S; Teodoro, Jose G.

doi:10.1038/cdd.2013.93

Cited by 45 publications

(49 citation statements)

References 57 publications

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“…In addition to this reduction in antiapoptotic signal, inhibition of Aurora A directly stabilizes BIM, increasing proapoptotic signalling. Others have shown that BIM depletion reduced the sensitivity of HeLa cells to Aurora A inhibitor (38), supporting the role for BIM in this Empty E7 lo E7 hi Figure 6. Expression of HPV E7 is sufficient to sensitize cells to Alisertib.…”

Section: Discussionsupporting

confidence: 57%

Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer

Gabrielli

Bokhari

Ranall

et al. 2015

Molecular Cancer Therapeutics

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Human papillomavirus (HPV) is the causative agent in cervical cancer. HPV oncogenes are major drivers of the transformed phenotype, and the cancers remain addicted to these oncogenes. A screen of the human kinome has identified inhibition of Aurora kinase A (AURKA) as being synthetically lethal on the background of HPV E7 expression. The investigational AURKA inhibitor MLN8237/Alisertib selectively promoted apoptosis in the HPV cancers. The apoptosis was driven by an extended mitotic delay in the Alisertib-treated HPV E7-expressing cells. This had the effect of reducing Mcl-1 levels, which is destabilized in mitosis, and increasing BIM levels, normally destabilized by Aurora A in mitosis. Overexpression of Mcl-1 reduced sensitivity to the drug.The level of HPV E7 expression influenced the extent of Alisertibinduced mitotic delay and Mcl-1 reduction. Xenograft experiments with three cervical cancer cell lines showed Alisertib inhibited growth of HPV and non-HPV xenografts during treatment. Growth of non-HPV tumors was delayed, but in two separate HPV cancer cell lines, regression with no resumption of growth was detected, even at 50 days after treatment. A transgenic model of premalignant disease driven solely by HPV E7 also demonstrated sensitivity to drug treatment. Here, we show for the first time that targeting of the Aurora A kinase in mice using drugs such as Alisertib results in a curative sterilizing therapy that may be useful in treating HPV-driven cancers.

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Section: Discussionsupporting

confidence: 57%

Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer

Gabrielli

Bokhari

Ranall

et al. 2015

Molecular Cancer Therapeutics

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“…The longest splice variant of Bim, Bim-EL, is phosphorylated on a number of sites by several kinases, including Erk and Rsk (Lei and Davis, 2003;Putcha et al, 2003;Ewings et al, 2007). Bim is phosphorylated in mitosis by Aurora A, regulating binding to the E3 ligase SCF-βTrCP1 (Moustafa-Kamal et al, 2013). This results in ubiquitination and degradation of Bim-EL, which would appear to contradict the observation that cells become primed in mitosis.…”

Section: Dynamic Regulation Of Priming During Mitosismentioning

confidence: 98%

Mitosis and mitochondrial priming for apoptosis

Pedley

Gilmore

2016

Biological Chemistry

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Cell division is a period of danger for cells, as inaccurate segregation of chromosomes can lead to loss of cell viability or aneuploidy. In order to protect against these dangers, cells ultimately initiate mitochondrial apoptosis if they are unable to correctly exit mitosis. A number of important chemotherapeutics exploit this response to delayed mitotic exit, but despite this, the molecular mechanism of the apoptotic timer in mitosis has proved elusive. Some recent studies have now shed light on this, showing how passage through the cell cycle fine-tunes a cell's apoptotic sensitivity such that it can respond appropriately when errors arise.

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“…SCF Fbxo10 has been implicated in BCL2 protein degradation and reported to be compromised by mutational inactivation or deletion in germinal center type DLBCL [24]. Similarly, the BCL2 family protein BIM is targeted for degradation by two E3 ligases namely βTrCP and APC CDC20 in different cellular contexts [25,26]. Overexpression of the BCL2 family protein myeloid-cell leukemia sequence 1 (MCL1), cooperates with Myc and to promote lymphomagenesis [127].…”

Section: Genotoxic Stress and Cellular Apoptosismentioning

confidence: 99%

The role of aberrant proteolysis in lymphomagenesis

Sahasrabuddhe

Elenitoba-Johnson²

2015

Current Opinion in Hematology

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Purpose of review Deregulated proteolysis is increasingly being implicated in pathogenesis of lymphoma. In this review, we highlight the major cellular processes that are affected by deregulated proteolysis of critical substrates that promote lymphoproliferative disorders. Recent findings Emerging evidences support the role of aberrant proteolysis by the ubiquitin proteasome system (UPS) in lymphoproliferative disorders. Several UPS mediators are identified to be altered in lymphomagenesis. However, the precise role of their alteration and comprehensive knowledge of their target substrate critical for lymphomagenesis is far from complete. Summary Many E3 ligase and Deubiquitinases that contribute to regulated proteolysis of substrates critical for major cellular processes are altered in various lineages of lymphoma. Understanding of the proteolytic regulatory mechanisms of these major cellular pathways may offer novel biomarkers and targets for lymphoma therapy.

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BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

Cited by 45 publications

References 57 publications

Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer

Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer

Mitosis and mitochondrial priming for apoptosis

The role of aberrant proteolysis in lymphomagenesis

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