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dc.contributor.author
Sabiani, Samaneh
dc.contributor.author
Geppert, Tim
dc.contributor.author
Engelbrecht, Christian
dc.contributor.author
Kowarz, Eric
dc.contributor.author
Schneider, Gisbert
dc.contributor.author
Marschalek, Rolf
dc.date.accessioned
2019-09-30T16:16:20Z
dc.date.available
2017-06-11T17:24:08Z
dc.date.available
2019-09-30T16:16:20Z
dc.date.issued
2015-05
dc.identifier.other
10.1016/j.ebiom.2015.04.009
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/100787
dc.identifier.doi
10.3929/ethz-b-000100787
dc.description.abstract
We have recently demonstrated that Taspase1-mediated cleavage of the AF4–MLL oncoprotein results in the formation of a stable multiprotein complex which forms the key event for the onset of acute proB leukemia in mice. Therefore, Taspase1 represents a conditional oncoprotein in the context of t(4;11) leukemia. In this report, we used site-directed mutagenesis to unravel the molecular events by which Taspase1 becomes sequentially activated. Monomeric pro-enzymes form dimers which are autocatalytically processed into the enzymatically active form of Taspase1 (αββα). The active enzyme cleaves only very few target proteins, e.g., MLL, MLL4 and TFIIA at their corresponding consensus cleavage sites (CSTasp1) as well as AF4–MLL in the case of leukemogenic translocation. This knowledge was translated into the design of a dominant-negative mutant of Taspase1 (dnTASP1). As expected, simultaneous expression of the leukemogenic AF4–MLL and dnTASP1 causes the disappearance of the leukemogenic oncoprotein, because the uncleaved AF4–MLL protein (328 kDa) is subject to proteasomal degradation, while the cleaved AF4–MLL forms a stable oncogenic multi-protein complex with a very long half-life. Moreover, coexpression of dnTASP1 with a BFP-CSTasp1-GFP FRET biosensor effectively inhibits cleavage. The impact of our findings on future drug development and potential treatment options for t(4;11) leukemia will be discussed.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Elsevier
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
t(4;11) leukemia
en_US
dc.subject
Taspase1
en_US
dc.subject
AF4–MLL
en_US
dc.subject
Oncoprotein activation
en_US
dc.title
Unraveling the Activation Mechanism of Taspase1 which Controls the Oncogenic AF4-MLL Fusion Protein
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
dc.date.published
2015-04-16
ethz.journal.title
EBioMedicine
ethz.journal.volume
2
en_US
ethz.journal.issue
5
en_US
ethz.pages.start
386
en_US
ethz.pages.end
395
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Amsterdam
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03852 - Schneider, Gisbert / Schneider, Gisbert
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03852 - Schneider, Gisbert / Schneider, Gisbert
ethz.date.deposited
2017-06-11T17:25:13Z
ethz.source
ECIT
ethz.identifier.importid
imp5936532ace07e77664
ethz.ecitpid
pub:158158
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-13T07:49:50Z
ethz.rosetta.lastUpdated
2019-09-30T16:16:39Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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