TY  - JOUR
A1  - Sabiani, Samaneh
A1  - Geppert, Tim
A1  - Engelbrecht, Christian
A1  - Kowarz, Eric
A1  - Schneider, Gisbert
A1  - Marschalek, Rolf
T1  - Unraveling the activation mechanism of taspase1 which controls the oncogenic AF4–MLL fusion protein
T2  - EBioMedicine
N2  - 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.
KW  - t(4;11) leukemia
KW  - Taspase1
KW  - AF4–MLL
KW  - Oncoprotein activation
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/77160
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-771608
SN  - 2352-3964
VL  - 2
IS  - 5
SP  - 386
EP  - 395
PB  - Elsevier
CY  - Amsterdam
ER  -