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Gewies, Andreas (2004): Investigation of the ubiquitin-specific protease UBP41 and of the lysosomal cysteine proteases cathepsin-L and cathepsin-B as potential mediators of proapoptotic signalling. Dissertation, LMU München: Faculty of Biology
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Abstract

Two projects are described within the scope of this thesis. The first project characterizes the ubiquitin-specific protease UBP41 as a protein which upon overexpression causes apoptosis induction in several mammalian cancer cell lines. The second project investigates a possible involvement of the lysosomal cysteine proteases cathepsin-L and cathepsin-B in apoptosis pathways induced by distinct death stimuli, in particular by the tumor necrosis factor a (TNF-a). Therefore, both projects examine a possible regulation of apoptosis induction by proteases that are part of one of the two major systems of protein degradation. UBP41 as a protease with deubiquitylating activity is expected to play a role in the ubiquitin/proteasome system which is the major proteolytic apparatus for the degradation of cytosolic proteins. Cathepsins, on the other hand, are lysosomal proteases that participate in the breakdown of membrane-associated proteins and of extracellular proteins that are taken up by endocytosis. Both, the ubiquitin/proteasome system as well as lysosomal proteases have been previously implicated in the regulation and mediation of apoptosis, and it therefore appeared particularly attractive to further study the effect of UBP41 and cathepsins on cell death signalling in more detail.

Abstract

Mittels eines genetischen cDNA Screening-Verfahren wurden neuartige, bislang noch nicht identifizierte dominant proapoptotische Faktoren isoliert. Darunter war ein cDNA Klon, welcher für die Ubiquitin-spezifische Protease UBP41 kodierte, sowie ein weiterer cDNA Klon, welcher für die lysosomale Protease Cathepsin-L kodierte. Es wurden im weiteren der proapoptotische Effekt von UBP41 sowie der mögliche Zusammenhang zwischen Cathepsin-Expressionsleveln und der Sensitiviät von Tumorzellen gegenüber Apoptose-Induktion studiert. Die Dissertation leistet einen Beitrag zu der in der aktuellen Apoptoseforschung intensiv diskutierten Fragestellung, ob und auf welche Weise Nicht-Caspase Cystein-Proteasen einen Einfluss auf die Vermittlung apoptotischer Signalwege haben.