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Research interests

Molekulare Medizin - AG Reinheckel
 
Signaling of cell death and survival

We are interested in a quite fundamental decision, made by any cell being a part of a multi-cellular eukaryotic system: whether it will continue to live, or rather die—for the benefit of the organism.
This decision is genetically determined: the cell death program of apoptosis is, just as cell growth, proliferation and differentiation, an integral component of life and it is absolutely required to facilitate and organize e.g. development, immune responses or organ renewal.
Induction of apoptosis is regulated either by cell surface receptors (e.g. FAS or TNFR1), directly instructing the cell to die, or by molecular sensors within the cell (BH3 only-proteins). Activation of BH3 only-proteins will result in the permeabilization of the outer mitochondrial membrane by mediating activation of the BCL-2 family proteins BAX and/or BAK. Antiapoptotic BCL-2 family members like BCL-2, BCL-xL or MCL-1 oppose permeabilization by sequestering propapototic BCL-2 family proteins. Mitochondrial outer membrane permeabilization, the central event of apoptosis induction through the intrinsic pathway, will lead to the activation of caspases. Caspases, when activated, will disintegrate the cell and shut down crucial cellular functions: the cell is dying, exhibiting the characteristic morphological features of apoptosis—and will be immediately engulfed by its neighbors.

Stimulation of growth factor receptors will mediate cell growth and proliferation, but also generate pro-survival signals in the cell, e.g. modulate apoptotic protein function or gene expression through, for example, MAPKinase or PI3Kinase pathways—the apoptotic machinery is under the control of growth factor signaling.
A number of BCL-2 family proteins are regulated directly or indirectly by serine/threonine kinases: BAD is phosphorylated and inactivated by pro-survival kinases, BIM is phosphorylated by ERK, leading to its ubiquitylation, and own recent work demonstrated that MCL-1 is subject to increased degradation after phosphorylation by GSK-3. Another example is the transcriptional induction of pro-apoptotic proteins (FasL and BIM) through FOXO3a, regulated by AKT.

In this lab, we are aiming at exploring the interaction of survival and death signaling. Currently, we are further investigating the regulation of the antiapoptotic protein MCL-1 and exploring the regulation of the BH3 only-protein PUMA by IL-3 induced signaling pathways.


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