@article{KruseShenArnoldetal.1993,
  author    = {Kruse, N. and Shen, B. J. and Arnold, S. and Tony, H. P. and M{\"u}ller, T. and Sebald, Walter},
  title     = {Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62451},
  year      = {1993},
  abstract  = {Interleukin 4 (IL-4) exerts a decisive role in the coord.ination of proteelive immune responses against parasites, particularly helminths. A disregulation of ll.r4 function is possibly involved in the genesis of allergic disease states. The search for important amino acid residues in human ll.r4 by mutational analysis of charged invariant amino acid positions identified two distinct functional sites in the 4-helix-bundle protein. Site 1 was marked by amino acid substitutions of the glutamic acid at position 9 in helix A and arginine at position 88 in helix C. Exchanges at both positions led to IL-4 variants deficient in binding to the extracellular domain of the ll.r4 receptor (IL-4ReJ. In parallel, up to 1000-fold increased concentrations of this type of variant were required to induce T -cell proliferation and B-eeil CD23 expression. Site 2 was marked by amino acid exchanges in helix D at positions 121, 124 and 125 (arginine, tyrosine and serine respectively in the wild-type).ß.A variants affected at site 2 exhibited partial agonist activity during T -cell proliferation; however, they still bound with high affinity to IL-4Rex. [The generation of an IL-4 antagonist by replacing tyrosine 124 with aspartic acid has been described before by Kruse et al. (1992) (EMBO }., 11, 3237-3244)]. These findings indicate that IL-4 functions by bind.ing IL-4Rex via site 1 which is constituted by residues on helices A and C. They further suggest that the association of a second, still undetined receptor protein with site 2 in helix D activates the receptor system and generates a transmembrane signal.},
  subject      = {Biochemie},
  language  = {en}
}
@article{PeterBultinckMyantetal.2014,
  author    = {Peter, Stefanie and Bultinck, Jennyfer and Myant, Kevin and Jaenicke, Laura A. and Walz, Susanne and M{\"u}ller, Judith and Gmachl, Michael and Treu, Matthias and Boehmelt, Guido and Ade, Casten P. and Schmitz, Werner and Wiegering, Armin and Otto, Christoph and Popov, Nikita and Sansom, Owen and Kraut, Norbert and Eilers, Martin},
  title     = {H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase},
  series = {EMBO Molecular Medicine},
  volume    = {6},
  journal   = {EMBO Molecular Medicine},
  number    = {12},
  issn      = {1757-4684},
  doi       = {10.15252/emmm.201403927},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118132},
  pages     = {1525-41},
  year      = {2014},
  abstract  = {Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.},
  language  = {en}
}
@article{ThornChaoGeorgievetal.2020,
  author    = {Thorn, Simon and Chao, Anne and Georgiev, Konstadin B. and M{\"u}ller, J{\"o}rg and B{\"a}ssler, Claus and Campbell, John L. and Jorge, Castro and Chen, Yan-Han and Choi, Chang-Yong and Cobb, Tyler P. and Donato, Daniel C. and Durska, Ewa and Macdonald, Ellen and Feldhaar, Heike and Fontaine, Jospeh B. and Fornwalt, Paula J. and Hern{\´a}ndez Hern{\´a}ndez, Raquel Mar{\´i}a and Hutto, Richard L. and Koivula, Matti and Lee, Eun-Jae and Lindenmayer, David and Mikusinski, Grzegorz and Obrist, Martin K. and Perl{\´i}k, Michal and Rost, Josep and Waldron, Kaysandra and Wermelinger, Beat and Weiß, Ingmar and Zmihorski, Michal and Leverkus, Alexandro B.},
  title     = {Estimating retention benchmarks for salvage logging to protect biodiversity},
  series = {Nature Communications},
  volume    = {11},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-020-18612-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230512},
  year      = {2020},
  abstract  = {Forests are increasingly affected by natural disturbances. Subsequent salvage logging, a widespread management practice conducted predominantly to recover economic capital, produces further disturbance and impacts biodiversity worldwide. Hence, naturally disturbed forests are among the most threatened habitats in the world, with consequences for their associated biodiversity. However, there are no evidence-based benchmarks for the proportion of area of naturally disturbed forests to be excluded from salvage logging to conserve biodiversity. We apply a mixed rarefaction/extrapolation approach to a global multi-taxa dataset from disturbed forests, including birds, plants, insects and fungi, to close this gap. We find that 757\% (mean +/- SD) of a naturally disturbed area of a forest needs to be left unlogged to maintain 90\% richness of its unique species, whereas retaining 50\% of a naturally disturbed forest unlogged maintains 73 +/- 12\% of its unique species richness. These values do not change with the time elapsed since disturbance but vary considerably among taxonomic groups. Salvage logging has become a common practice to gain economic returns from naturally disturbed forests, but it could have considerable negative effects on biodiversity. Here the authors use a recently developed statistical method to estimate that ca. 75\% of the naturally disturbed forest should be left unlogged to maintain 90\% of the species unique to the area.},
  language  = {en}
}
@article{OttoSchmidtKastneretal.2019,
  author    = {Otto, C. and Schmidt, S. and Kastner, C. and Denk, S. and Kettler, J. and M{\"u}ller, N. and Germer, C.T. and Wolf, E. and Gallant, P. and Wiegering, A.},
  title     = {Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells},
  series = {Neoplasia},
  volume    = {21},
  journal   = {Neoplasia},
  number    = {11},
  doi       = {10.1016/j.neo.2019.10.003},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202451},
  pages     = {1110-1120},
  year      = {2019},
  abstract  = {The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.},
  language  = {en}
}
@article{MuellerCosentinoFoerstneretal.2018,
  author    = {M{\"u}ller, Laura S. M. and Cosentino, Ra{\´u}l O. and F{\"o}rstner, Konrad U. and Guizetti, Julien and Wedel, Carolin and Kaplan, Noam and Janzen, Christian J. and Arampatzi, Panagiota and Vogel, J{\"o}rg and Steinbiss, Sascha and Otto, Thomas D. and Saliba, Antoine-Emmanuel and Sebra, Robert P. and Siegel, T. Nicolai},
  title     = {Genome organization and DNA accessibility control antigenic variation in trypanosomes},
  series = {Nature},
  volume    = {563},
  journal   = {Nature},
  doi       = {10.1038/s41586-018-0619-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224265},
  pages     = {121-125},
  year      = {2018},
  abstract  = {Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host1. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility2,3. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding4. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses—Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing—that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.},
  language  = {en}
}