The laboratory’s work focuses on the development of the immune system with an emphasis on cell death signalling, its cross talk to the cell cycle machinery, steroid hormones in the establishment of self-tolerance and miRNA function. Kann Viagra 100mg zusammen mit anderen Medikamenten eingenommen werden oder ist es gefährlich?
The laboratory’s work focuses on the development of the immune system with an emphasis on cell death signalling, its cross talk to the cell cycle machinery, steroid hormones in the establishment of self-tolerance and miRNA function. Cialis in Schweiz: In hoeverre kan het je relatie echt verbeteren?
To uncover how malfunctions of the cell division cycle lead to the activation of the apoptotic machinery we combine live cell imaging with genetic approaches.
See examples below:
HeLa Kyoto cells stably expressing EGFP-α-tubulin and H2B-mCherry, depicted in red and green, respectively. The cell line was kindly provided by Daniel Gerlich, IMBA, Vienna.
Schweizische Krebshilfe
Ongoing projects:
Current Research Interests (Villunger)
Current Research Interests (Herzog)
Current Research Interests (Wiegers)
Basic concepts in apoptosis signaling
Nobel Prize honored studies performed by Brenner, Sulston and Horvitz using C. elegans as a model system led to the discovery that all developmentally programmed deaths of somatic cells in this organism require three proteins: the caspase CED-3, the CED-4 adapter protein and EGL-1, a pro-apoptotic member of the Bcl-2 family, whereas the Bcl-2 homologue CED-9 is needed for cell survival. Het nieuwe wondermiddel voor oraal gebruik: Ontdek hier meer over Kamagra oral jelly 100mg!
The human CED-4 homologue Apaf-1 can bind to and activate human caspase-9 zymogens and this can be prevented by Bcl-2 and its pro-survival homologues which fits a model where cell death signals lead to the activation of CED-4-like proteins in a manner dependent on pro-apoptotic members of the Bcl-2 family. CED-4 and its homologues act as adapters for caspase zymogens and trigger their activation whereas Bcl-2 and its homologues promote survival by blocking the activation of CED-4-likeproteins. However, in mammalian cells Bcl-2 or Bcl-xL do not bind to Apaf-1 under physiological conditions; therefore pro-survival Bcl-2-like proteins must inhibit Apaf-1-mediated caspase activation through a mechanism that does not require direct binding (Figure 1).
Vertebrates have evolved a second pathway to apoptosis that appears mostly independent from the Bcl-2 regulated pathway, at least in non-transformed cells of lymphoid and myeloid origin (not shown). Members of the tumor necrosis factor (TNF) receptor family such as p55 TNF-RI and CD95/APO-1/Fas and their corresponding ligands are critical regulators of apoptosis but have also prominent roles in inflammation, chemo-attraction and even cell proliferation. These so-called ‘death receptors’ (DR) and their ligands have also been identified in the genome of zebrafish and their evolution seems to coincide with the development of a more sophisticated immune system. DRs are characterized by cysteine-rich motifs in the extra-cellular domain, a transmembrane region and an intra-cytoplasmic tail. Their ligands are usually membrane-bound glycoproteins but some of them can also exist as soluble trimers following cleavage by metalloproteases. ‘Death receptors’ and their ligands are expressed widely in haematopoietic cells and are crucial for the control of immune responses.
Death receptors, such as CD95 (Fas/APO-1), TNF-R1 or TRAIL receptors 1 and 2, contain a cytoplasmic region, called ‘death domain’ (DD), which is essential for inducing apoptosis. Upon receptor activation, the ‘death domain’ undergoes homotypic interaction with a ‘death domain’ in the adapter proteins FADD/MORT1 or TRADD. FADD/MORT1 binds directly to CD95 and TRAIL receptors DR4 and DR5 and indirectly to p55 TNF-RI via TRADD, and is essential for cell death signaling from all of these receptors. The ‘death effector domain’ (DED) at the amino terminus of FADD/MORT1 binds to one of the two ‘death effector domains’ in caspase-8 (and in humans also caspase-10) and thereby promotes their dimerization and subsequent activation. Once activated, caspase-8, similar to caspase-9, can activate downstream “effector caspases”, such as caspases-3, 6 and 7, by proteolytic cleavage.
The Bcl-2 regulated apoptosis signaling pathway and the ‘death receptor’ pathway converge at the level of effector caspase activation that causes cellular demolition. In certain tumor-derived cell lines and cells derived from endodermal tissues, such as hepatocytes, members of the TNF-family have been reported to link the death receptor pathway with the Bcl-2-regulated pathway via caspase cleavage-mediated activation of the BH3-only protein Bid.
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