Die Bedeutung von A20 und ABIN-1 für die TNF-vermittelte apoptotische und inflammatorische Signalgebung von Keratinozyten
Final Report Abstract
In summary, we have investigated by methods of molecular biology and biochemistry the role of A20 in TNF signaling pathways in human and murine keratinocytes in vitro as well as in vivo. We have discovered unexpected role of A20 in promoting TNF-induced cell death. We could analyze the interplay between NF-κB signaling and A20-induced cell death in keratinocytes from human and mice origin. Furthermore, we revealed the crucial obstructive role of A20 for the formation and function of TNF complex I and at the same time critical promoting role for Ripoptosome formation. Additionally, to analyze the functional role of A20 in human cells we used Cas9/CRISPR system for A20 knock out. Moreover our in vivo experimental studies demonstrated encouraging results showing critical role A20 for the skin homeostasis. Further detailed analyses of this in vivo model will be performed during following projects.
Publications
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(2011) Cellular FLICE-inhibitory protein (cFLIP) isoforms block CD95- and TRAIL death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the deathinducing signaling complex. J Biol Chem. May 13;286(19)
Kavuri SM, Geserick P, Berg D, Dimitrova DP, Feoktistova M, Siegmund D, Gollnick H, Neumann M, Wajant H, Leverkus M
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(2012) Autophagy inhibition due to thymidine analogues as novel mechanism leading to hepatocyte dysfunction and lipid accumulation. AIDS. 23; 26(16)
Stankov MV, Panayotova-Dimitrova D, Leverkus M, Vondran FW, Bauerfeind R, Binz A, Behrens GM
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(2013) cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 31;5(2)
Panayotova-Dimitrova D, Feoktistova M, Ploesser M, Kellert B, Hupe M, Horn S, Makarov R, Jensen F, Porubsky S, Schmieder A, Zenclussen AC, Marx A, Kerstan A, Geserick P, He YW, Leverkus M
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(2013) Thymidine analogues suppress autophagy and adipogenesis in cultured adipocytes. Antimicrob Agents Chemother. 57(1):543-51
Stankov MV, Panayotova-Dimitrova D, Leverkus M, Schmidt RE, Behrens GM
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(2014) Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. Leukemia 28(3)
Stankov MV, El Khatib M, Kumar Thakur B, Heitmann K, Panayotova-Dimitrova D, Schoening J, Bourquin JP, Schweitzer N, Leverkus M, Welte K, Reinhardt D, Li Z, Orkin SH, Behrens GM, Klusmann JH
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(2015) Absence of RIPK3 predicts necroptosis resistance in malignant melanoma. Cell Death Dis. Sep 10;6
Geserick P, Wang J, Schilling R, Horn S, Harris PA, Bertin J, Gough PJ, Feoktistova M, Leverkus M
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The ratio of Mcl-1 and Noxa determines ABT737 resistance in squamous cell carcinoma of the skin (2015) Cell Death Dis. Mar 5;6
Geserick P, Wang J, Feoktistova M, Leverkus M
