Living organisms can modify their proteins through posttranslational modifications. By this means, the reversible, dynamic and without a new protein synthesis repertoire of protein functions can be substantially enlarged. Cells produce several enzymes which catalyse protein modifications constitutively or after induction through several external stimuli. Aberrant protein modifications are associated with cancer and other severe diseases. In my project group, we analyse the relevant proteins for the tumorigenesis with respect to their acetylation, methylation and ubiquitinylation.
The starting point provides an epigenetically modified chromatin structure through external stimuli (the yellow circles indicate, for example, acetylation and methylation of lysine residues) (1). Transcriptional regulators direct gene expression. For example, the stress modules ATM-CHK2/ATR-CHK1 regulate tumour suppressor p53.
Genotoxic agents and replicative stress can trigger ambivalent cellular programs related to these factors, for instance, induction of NF-κB target genes for repair processes and the programmed cell death by p53 (P for phosphorylation; Ac for acetylation) (2). The activation of the transcription factor STAT1 induced by interferons is modulated via phosphorylation-acetylation switches to tyrosine and lysine residues.
In turn, Acetyl-STAT1 inhibits NF-kB. This results in regulation loops which are essential for the survival of the tumour cells (3). The covalent posttranslational modification of the lysine deacetylase HDAC2 with SUMO1 (small ubiquitin-related modifier 1) inhibits signal transduction operating through p53 (4). HDACi and interferons induce the E2 ubiquitin conjugating enzyme UBCH8. UBCH8 catalyses the selective proteasomal cleavage of proteins, together with E3 ubiquitin ligases RLIM or SIAH. By these means, the expression as well as the activity of HDAC2 are blocked. Negative feedback in the STAT proteins on the cleavage of tumour-relevant tyrosine kinases is possible with the induction of UBCH8 (JAKs; ACK1; ITD) (5). They are also involved in oxidative stress phenomena. One focus of the analysis lies on casual chains which ultimately determine the transcription of critical proteins (symbolised by x and y) and cellular fate such as decisions between repair, cell cycle blockade, senescence and apoptosis. The bottom row shows different apoptosis regulators (red/green: pro- or anti-apoptotic) (6).
Buchwald M., Pietschmann K., Brand P., Günther A., Mahajan N., Heinzel T., Krämer O. (2013) SIAH ubiquitin ligases target the nonreceptor tyrosine kinase ACK1 for ubiquitinylation and proteasomal degradation, Oncogene, 32, 4913-4920
Brandl A., Wagner T., Uhlig K., Knauer S., Stauber R., Melchior F., Schneider G., Heinzel T., Krämer O. (2012)Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress, Journal of Molecular and Cellular Biology, 4, 284-293
Stauber R., Knauer S., Habtemichael N., Bier C., Unruhe B., Weisheit S., Spange S., Nonnenmacher F., Fetz V., Ginter T., Reichardt S., Liebmann C., Schneider G., Krämer O. (2012) A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer, Oncotarget, 2012, 3, 31-43
Buchwald M., Pietschmann K., Müller J., Heinzel T., Böhmer F., Krämer O. (2010) The ubiquitin-conjugase UBCH8 targets oncogenic FMS-like tyrosine kinase 3 for proteasomal degradation, Leukemia, 24, 1412-1421
Schneider G., Henrich A., Greiner G., Wolf V., Reichardt S., Wieczorek M., Wagner T., von Werder A., Schmid R., Weih F., Heinzel T., Saur D., Krämer O. (2010) Cross talk between stimulated NF-κB and the tumor suppressor p53, Oncogene, 29, 2795-2806