Overexpression of the catalytically impaired Taspase1 T234V or Taspase1 D233A variants does not have a dominant negative effect in T(4;11) leukemia cells.

PloS One
Carolin BierRoland H Stauber

Abstract

The chromosomal translocation t(4;11)(q21;q23) is associated with high-risk acute lymphoblastic leukemia of infants. The resulting AF4•MLL oncoprotein becomes activated by Taspase1 hydrolysis and is considered to promote oncogenic transcriptional activation. Hence, Taspase1's proteolytic activity is a critical step in AF4•MLL pathophysiology. The Taspase1 proenzyme is autoproteolytically processed in its subunits and is assumed to assemble into an αββα-heterodimer, the active protease. Therefore, we investigated here whether overexpression of catalytically inactive Taspase1 variants are able to interfere with the proteolytic activity of the wild type enzyme in AF4•MLL model systems. The consequences of overexpressing the catalytically dead Taspase1 mutant, Taspase1(T234V), or the highly attenuated variant, Taspase1(D233A), on Taspase1's processing of AF4•MLL and of other Taspase1 targets was analyzed in living cancer cells employing an optimized cell-based assay. Notably, even a nine-fold overexpression of the respective Taspase1 mutants neither inhibited Taspase1's cis- nor trans-cleavage activity in vivo. Likewise, enforced expression of the α- or β-subunits showed no trans-dominant effect against the ectopically or endogenou...Continue Reading

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Citations

Jan 19, 2016·Oral Oncology·Angelina HahlbrockRoland H Stauber
Nov 19, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Roland H StauberDésirée Wünsch
Jan 31, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Désirée WünschRoland H Stauber
Mar 31, 2021·Structure·Nirupa NagaratnamJose M Martin-Garcia

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Methods Mentioned

BETA
ubiquitination
genetic interference
PCR
Transfection
protein
interaction assay
gel filtration
size exclusion chromatography
biosensor
fluorescence microscopy

Software Mentioned

colocalizer
Tasp Cyt

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