@article{KruseTonySebald1992,
author = {Kruse, N. and Tony, H. P. and Sebald, Walter},
title = {Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62469},
year = {1992},
abstract = {lnterleukin-4 (IL-4) represents a prototypic lymphokine (for a recent review see Paul, 1991). It promotes differentiation of B-cells and the proliferation of T- and B-cell, and other cell types of the lymphoid system. An antagonist of human IL-4 was discovered during the studies presented here after Tyr124 of the recombinant proteinbad been substituted by an aspartic acid residue. This IL-4 variant, Y124D, bound with high affinity to the IL-4 receptor (K\(_D\) = 310 pM), but retained no detectable proliferative activity for T -<:ells and inhibited IL-4-dependent T -cell proliferation competitively (K\(_i\) = 620 pM). The loss of efficacy in variant Y124D was estimated to be > 100-fold on the basis of a weak partial agonist activity for the very sensitive induction of CD23 positive B-cells. The subsitution of Tyr124 by either phenylalanine, histidine, asparagine, Iysine or glycine resulted in partial agonist variants with unaltered receptor binding atTmity and relatively small deficiencies in efficacy. These results demoostrate that high affinity binding and signal generation can be uncoupled efticiently in a Iigand of a receptor betonging to the recently identified hematopoietin receptor family. In addition we show for the first time, that a powerful antagonist acting on the IL-4 receptor system can be derived from the IL-4 protein.},
subject = {Biochemie},
language = {en}
}
@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{MuellerDieckmannSebaldetal.1994,
author = {M{\"u}ller, T. and Dieckmann, T. and Sebald, Walter and Oschkinat, H.},
title = {Aspects of receptor binding and signalling of interleukin-4 investigated by site-directed mutagenesis and NMR spectroscopy},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62444},
year = {1994},
abstract = {Cytokines are hormones that carry information from ceJI to ceH. This information is read from their surface upon binding to transmembrane receptors and by the subsequent initiation of receptor oligomerization. An inftuence on this process through mutagenesis on the hormone surface is highly desirab)e for medical reasons. However, an understanding of hormone-receptor interactions requires insight into the structural changes introduced by the mutations. In this line structural studies on human TL-4 and the medically important IL-4 antagonists YI24D and Y124G are presented. The site a.round YI24 is an important epitope responsible for the a.bility of 11-4 t.o ca.use a signal in the target cells. It is shown that the local main-chain structure around residue 124 in the variants remains unchanged. A strategy is presented here which allows the study of these types of proteins and their variants by NMR which does not require carbon Iabeiied sa.mples.},
subject = {Biochemie},
language = {en}
}
@article{LehrnbecherPootOrschescheketal.1994,
author = {Lehrnbecher, T. and Poot, M. and Orscheschek, K. and Sebald, Walter and Feller, A. C. and Merz, H.},
title = {Interleukin 7 as interleukin 9 drives phytohemagglutinin-activated T cells through several cell cycles; no synergism between interleukin 7, interleukin 9 and interleukin 4},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62438},
year = {1994},
abstract = {The effects of the interlenkins IL-7 and IL-9 on cell cycle progression were investigated by conventional [3H]thymidine incorporation and by the bivariate BrdU/Hoechst technique. 8oth IL· 7 and IL-9 drive phytohemagglutinin-activated T cells through more than one cell cycle, but IL-7 wasmorepotent on cell cycle progression than IL-9. Neither synergistic nor inhibitory effects were seen between various combinations of the lymphokines IL-7, IL-9 and IL-4 compared to each lymphokine alone. When T cells are activated with phytohemagglutinin for 3 days, all or most IL-4 responsive cells respond to IL-7 as weil, whereas only a part of IL-7 responders are IL-4 responders. In contrast, when T cells are activated with phytohemagglutinin for 7 days, the quantitative data of the cell cycle distribution soggest that the population of IL-7 responders is at least an overlapping, if not a real subset of the population of the IL-4 responders.},
subject = {Biochemie},
language = {en}
}
@article{DemchukMuellerOschkinatetal.1994,
author = {Demchuk, E. and Mueller, T. and Oschkinat, H. and Sebald, Walter and Wade, R. C.},
title = {Receptor binding properties of four-helix-bundle growth factors deduced from electrostatic analysis},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62424},
year = {1994},
abstract = {Hormones of the hematopoietin class mediate signal transduction by binding to specific transmembrane receptors. Structural data show that the human growth hormone (hGH) forms a complex with a homodimeric receptor and that hGH is a member of a class of hematopoietins possessing an antiparallel 4-a-helix bundle fold. Mutagenesis experiments suggest that electrostatic interactions may have an important influence on hormonereceptor recognition. In order to examine the specificity of hormone-receptor complexation, an analysis was made of the electrostatic potentials of hGH, interleukin-2 (IL-2), interleukin-4 (IL-4), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the hGH and IL-4 receptors. The binding surfaces of hGH and its receptor, and of IL-4 and its receptor, show complementary electrostatic potentials. The potentials of the hGH and its receptor display approximately 2-fold rotational symmetry because the receptor subunits are identical. In contrast, the potentials of GM-CSF and IL-2 Iack such symmetry, consistent with their known high affinity for hetero-oligomeric receptors. Analysis of the electrostatic potentials supports a recently proposed hetero-oligomeric model for a high-affinity IL-4 receptor and suggests a possible new receptor binding mode for G-CSF; it also provides valuable information for guiding structural and mutagenesis studies of signal-transducing proteins and their receptors.},
subject = {Biochemie},
language = {en}
}
@article{ReuschArnoldHeusseretal.1994,
author = {Reusch, P. and Arnold, S. and Heusser, C. and Wagner, K. and Weston, B. and Sebald, Walter},
title = {Neutralizing monoclonal antibodies define two different functional sites in human interleukin-4},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62418},
year = {1994},
abstract = {Human interleukin-4 (IL-4) is a small four-helix-bundle protein which is essential for organizing defense reactions against macroparasites, in particular helminths. Human IL-4 also appears to exert a pathophysiological role during various IgE-mediated allergic diseases. Seven different monoclonal antibodies neutralizing the activity of human IL-4 were studied in order to identify functionally important epitopes. A collection of 41 purified IL-4 variants was used to analyse how defined amino acid replacements affect binding affinity for each individual mAb. Specific amino acid positions could be assigned to four different epitopes. mAbs recognizing epitopes on helix A and/or C interfered with IL-4 receptor binding and thus inhibited IL-4 function. However, other mAbs also inhibiting IL-4 function recognized an epitope on helix D of IL-4 and did not inhibit IL-4 binding to the receptor protein. One mAb, recognizing N-terminal and C-terminal residues, partially competed for binding to the receptor. The results of these mAb epitope analyses confirm and extend previous data on the functional consequences of the amino acid replacements which showed that amino acid residues in helices A and C of IL-4 provide a binding site for the cloned IL-4 receptor and that a signalling site in helix D interacts with a further receptor protein.},
subject = {Biochemie},
language = {en}
}
@article{MuellerSebaldOschkinat1994,
author = {M{\"u}ller, T. and Sebald, Walter and Oschkinat, H.},
title = {Antagonist design through forced electrostatic mismatch},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62408},
year = {1994},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{TonyShenReuschetal.1994,
author = {Tony, H. P. and Shen, B. J. and Reusch, P. and Sebald, Walter},
title = {Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62394},
year = {1994},
abstract = {Human interleukin-4 possesses two distinct sites for receptor activation. A signaHing site, comprising residues near the C-terminus on helix D, determines the efficacy of interleukin-4 signal transduction without affecting the binding to the interleukin-4 receptor a subunit. A complete antagonist and a series of low-efficacy agonist variants of human interleukin-4 could be generated by introducing combinations of two or three negatively charged aspartic acid residues in this site at positions 121, 124, and 125. One of the double variants, designated [R121D,Y124D]interleukin-4, with replacements of b{\"o}th Arg121 and Tyr124 by aspartic acid residues was completely inactive in all analysed cellular responses. The loss of efficacy in [R121D,Y124D]interleukin-4 is estimated to be larger than 2000-fold. Variant [R121D,Y124D]interleukin-4 was also a perfect antagonist for inhibition of interleukin-13-dependent responses in B-cells and the TF-1 cellline with a K\(_i\) value of approximately 100 pM. In addition, inhibition of both interleukin-4-induced and interleuk.in-13- induced responses could be obtained by monoclonal antibody X2/45 raised against interleukin-4Rm the extracellular domain of the interleuk.in-4 receptor a subunit. These results indicate that efficient interleukin-4 antagonists can be designed on the basis of a sequential two-step activation model. In addition, the experiments indicate the functional participation of the interleukin-4 receptor a subunit in the interleukin-13 receptor system.},
subject = {Biochemie},
language = {en}
}
@article{KueblerReutherKirchneretal.1994,
author = {K{\"u}bler, N. and Reuther, J. and Kirchner, T. and Pfaff, M. and M{\"u}ller-Hermelink, H. K. and Albert, R. and Sebald, Walter},
title = {IgG monoclonal antibodies that inhibit osteoinductivity of human bone matrix-derived proteins (hBMP/NCP)},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62388},
year = {1994},
abstract = {Monoclonal hBMP/NCP (human bone morphogenetic protein anrl associaterl noncollagenous proteins) antiborlies of the lgG class were prorlucerl. In vitro, 12 of 19 hBMP/NCP antiborlies showerl functional inhibition of hBMP/ NCP-induced chondroneogenesis in a neonatal muscle tissue assay. Inducing factors were characterized by their inhibiting antibodies with immunoblotting. Several peptide factors seem to be involved in the cascade of inducerl chondro- and osteogenesis.},
subject = {Biochemie},
language = {en}
}
@article{GesslerBarnekow1984,
author = {Gessler, Manfred and Barnekow, Angelika},
title = {Differential expression of the cellular oncogenes c-src and c-yes in embryonal and adult chicken tissues},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59289},
year = {1984},
abstract = {The cellular onc-genes c-src and c-yes are expressed very differently during chicken embryonic development. The c-src mRNA and its translational product are detectable at high levels in brain extracts of chicken embryos and adult chickens, whereas muscle extracts show an age-dependent decrease in the amounts of c-src-specific mRNA and pp60c-src kinase activity. In contrast, the Ievels of c-yes mRNA in brain, heart, and muscle are relatively low in early embryonic stages and increase later on to values comparable to those found for liver, while in adult animals the pattern of c-yes expression is similar to that of the c-src gene. From the close correlation between the Ievels of pp60c-src, its enzymatic activity, and its corresponding mRNA at a given stage of development and in given tissues, it appears that the expression of pp60c-src is primarily controlled at the level of transcription. It is suggested that because of the different patterns of expression, the two cellular oncogenes, c-src and c-yes, play different roles in cell proliferation during early embryonic stages as weil as in ensuing differentiation processes.},
subject = {Biochemie},
language = {en}
}
@article{BarnekowGessler1986,
author = {Barnekow, Angelika and Gessler, Manfred},
title = {Activation of the pp60\(^{c-src}\) kinase during differentiation of monomyelocytic cells in vitro},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59278},
year = {1986},
abstract = {Tbe proto-oncogene c-src, the cellular homolog of the Rous sarcoma virus (RSV) transforming gene v-src, is expressed in a tissue-specific and age-dependent manner. Its physiological function, although still unknown, appears to be more closely related to differentiation processes than to proliferation processes. To obtain more information about the physiological role of the c-src gene in cells, we have studied differentiation-dependent alterations using the human HL-60 leukaemia cell line as a model system. Induction of monocytic and granulocytic differentiation of HL-60 cells by 12-0-tetradecanoylphorbol-13-acetate (TPA) and dimethylsulfoxide (DMSO) is associated with an activation of the pp60c-src tyrosine kinase, but not with increased c-src gene expression. Control experiments exclude an interaction of TPA and DMSO themselves with the pp60c-src kinase.},
subject = {Biochemie},
language = {en}
}
@article{GesslerBruns1988,
author = {Gessler, Manfred and Bruns, Gail A. P.},
title = {Molecular mapping and cloning of the breakpoints of a chromosome 11p14.1-p13 deletion associated with the AGR syndrome},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59264},
year = {1988},
abstract = {Chromosome 11p13 is frequently rearranged in individuals with the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) or parts of this syndrome. To map the cytogenetic aberrations molecularly, we screened DNA from cell Unes with known WAGR-related chromosome abnormalities for rearrangements with pulsed fleld gel (PFG) analysis using probes deleted from one chromosome 11 homolog of a WAGR patient. The first alteration was detected in a cell line from an individual with aniridia, genitourinary anomalies, mental retardation, and a deletion described as 11p14.1-p13. We have located one breakpoint close to probe HU11-164B and we have cloned both breakpoint sites as well as the junctional fragment. The breakpoints subdivide current intervals on the genetic map, and the probes for both sides will serve as important additional markers for a long-range restriction map of this region. Further characterization and sequencing of the breakpoints may yield insight into the mechanisms by which these deletions occur.},
subject = {Biochemie},
language = {en}
}
@article{GesslerThomasCouillinetal.1989,
author = {Gessler, Manfred and Thomas, G. H. and Couillin, P. and Junien, C. and McGillivray, B. C. and Hayden, M. and Jaschek, G. and Bruns, G. A.},
title = {A deletion map of the WAGR region on chromosome II},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59255},
year = {1989},
abstract = {The WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) region has been assigned to chromosome 11p13 on the basis of overlapping constitutional deletions found in affected individuals. We have utilized 31 DNA probes which map to the WAGR deletion region, together with six reference loci and 13 WAGR-related deletions, to subdivide this area into 16 intervals. Specific intervals have been correlated with phenotypic features, leading to the identification of individual subregions for the aniridia and Wilms tumor loci. Delineation, by specific probes, of multiple intervals above and below the critical region and of five intervals within the overlap area provides a framework map for molecular characterization of WAGR gene loci and of deletion boundary regions.},
subject = {Biochemie},
language = {en}
}
@article{GesslerBruns1989,
author = {Gessler, Manfred and Bruns, G. A. P.},
title = {A physical map around the WAGR complex on the short arm of chromosome 11},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59246},
year = {1989},
abstract = {A long-range restriction map of part of the short arm of ehromosome 11 including the WAGR region has been constructed using pulsed-field gel electrophoresis and a number of infrequently cutting restriction enzymes. A total of 15.4 Mbp has been mapped in detall, extending from proximal 11p14 to the distal part of 11p12. The map localizes 35 different DNA probes and reveals at least nine areas with features eharaeteristle of BTF islands, some of which may be candidates for the different loci underlying the phenotype of the WAGR syndrome. This map will furthermore allow screening of DNA from individuals with WAGR-related phenotypes and from Wilms tumors for associated chromosomal rearrangements.},
subject = {Biochemie},
language = {en}
}
@article{vanHeyningenBickmoreSeawrightetal.1990,
author = {van Heyningen, V. and Bickmore, W. A. and Seawright, A. and Fletcher, J. M. and Maule, J. and Fekete, G. and Gessler, Manfred and Bruns, G. A. and Huerre-Jeanpierre, C. and Junien, C.},
title = {Role for the Wilms tumor gene in genital development?},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59238},
year = {1990},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{GesslerHameisterHenryetal.1990,
author = {Gessler, Manfred and Hameister, H. and Henry, I. and Junien, C. and Braun, T. and Arnold, H. H.},
title = {The human MyoD1 (MYF3) gene maps on the short arm of chromosome 11 but is not associated with the WAGR locus or the region for the Beckwith-Wiedemann syndrome},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59221},
year = {1990},
abstract = {The human gene encoding the myogenic determination factor myf3 (mouse MyoD1) has been mapped to the short arm of chromosome 11. Analysis of several somatic cell hybrids containing various derivatives with deletions or translocations revealed that the human MyoD (MYF3) gene is not associated with the WAGR locus at chromosomal band 11pl3 nor with the loss of the heterozygosity region at 11p15.5 related to the Beckwith-Wiedemann syndrome. Subregional mapping by in situ hybridization with an myf3 specific probe shows that the gene resides at the chromosomal band llp14, possibly at llp14.3.},
subject = {Biochemie},
language = {en}
}
@article{VortkampThiasGessleretal.1991,
author = {Vortkamp, A. and Thias, U. and Gessler, Manfred and Rosenkranz, W. and Kroisel, P. M. and Tommerup, N. and Kruger, G. and Gotz, J. and Pelz, L. and Grzeschik, Karl-Heinz},
title = {A somatic cell hybrid panel and DNA probes for physical mapping of human chromosome 7p},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59217},
year = {1991},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{WolfKlugHackenbergetal.1992,
author = {Wolf, Markus and Klug, J{\"o}rg and Hackenberg, Reinhard and Gessler, Manfred and Grzeschik, Karl-Heinz and Beato, Miguel and Suske, Guntram},
title = {Human CC10, the homologue of rabbit uteroglobin: genomic cloning, chromosomal localization and expression in endometrial cell lines},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59206},
year = {1992},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{GesslerKoenigBruns1992,
author = {Gessler, Manfred and K{\"o}nig, A. and Bruns, G. A. P.},
title = {The genomic organization and expression of the WT1 gene},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59195},
year = {1992},
abstract = {The Wilms tumor gene WTl, a proposed tumor suppressor gene, has been identifled based on its location within a homozygous deletion found in tumor tissue. The gene encodes a putative transcription factor containing a Cys/His zinc finger domain. The critical homozygous deletions, however, are rarely seen, suggesting that in many cases the gene may be inactivated by more subtle alterations. To facilitate the seareh for smaller deletions and point mutations we have established the genomic organization of the WTl gene and have determined the sequence of all 10 exons and flanking intron DNA. The pattern of alternative splicing in two regions has been characterized in detail. These results will form the basis for future studies of mutant alleles at this locus.},
subject = {Biochemie},
language = {en}
}
@article{GesslerGrupeGrzeschiketal.1992,
author = {Gessler, Manfred and Grupe, Andrew and Grzeschik, Karl-Heinz and Pongs, Olaf},
title = {The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59184},
year = {1992},
abstract = {Transiently activating (A-type) potassium (K) channels are important regulators of action potential and action potential firing frequencies. HK1 designates the firsthuman cDNA that is highly homologous to the rat RCK4 cDNA that codes for an A-type K-channel. The HK1 channel is expressed in heart. By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-pl4, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation). Subsequent pulsed field gel (PFG) analysis and comparison with the well-established PFG map of this region localized the gene to 11p14, 200-600 kb telomeric to the FSHB gene.},
subject = {Biochemie},
language = {en}
}
@article{PoulatMorinKonigetal.1993,
author = {Poulat, F. and Morin, D. and Konig, A. and Brun, P. and Giltay, J. and Sultan, C. and Dumas, R. and Gessler, Manfred and Berta, P.},
title = {Distinct molecular origins for Denys-Drash and Frasier syndromes},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59172},
year = {1993},
abstract = {The direct involvment of the Wilm's tumor suppressor gene (WTl) in Denys-Drash syndrome through mutations within exons 8 or 9 has recently been established. The absence of such alterations in three patients with Frasier syndrome provides a molecular basis for distinguishing these two syndromes that are associated with streak gonads, pseudohermaphroditism and renal failure.},
subject = {Biochemie},
language = {en}
}
@article{KonigJakubiczkaWieackeretal.1993,
author = {Konig, Anja and Jakubiczka, Sybille and Wieacker, Peter and Schl{\"o}sser, Hans W. and Gessler, Manfred},
title = {Further evidence that imbalance of WT1 isoforms may be involved in Denys-Drash syndrome},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59167},
year = {1993},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{HenryHooversBarichardetal.1993,
author = {Henry, Isabelle and Hoovers, Jan and Barichard, Fernande and Berth{\´e}as, Marie-Francoise and Puech, Anne and Prieur, Fabienne and Gessler, Manfred and Bruns, Gail and Mannens, Marcel and Junien, Claudine},
title = {Pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in a family},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59157},
year = {1993},
abstract = {The combined use of qualitative and quantitative analysis of I I p I 3 polymorphic markers tagether with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to I I p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible (or recurrence of del( I I )(p 13p 14) in the family: an insertion of band I I p 13-p 14 carrying the genes for predisposition to Wilms' tumor, WT I, and for aniridia, AN2, into the long arm of chromosome I I in II q 13-q 1<4. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del( II )(p 13). Two of these women gave birth to children carrying a deleted chromosome II. most likely resulting from the loss of the I I p 13 band inserted in I I q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide Variation in clinical expression. One child, with the karyotype 46,XY,del(ll)(pllpl4), presented the full-blown WAGR syndrome with anlridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del( I I )(p I 3), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WTI gene can result in similar genital and kidney abnormalities.},
subject = {Biochemie},
language = {en}
}
@article{GesslerKonigMooreetal.1993,
author = {Gessler, Manfred and Konig, Anja and Moore, Jay and Qualman, Steven and Arden, Karen and Cavenee, Webster and Bruns, Gail},
title = {Homozygous inactivation of WTI in a Wilms' tumor associated with the WAGR syndrome},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59146},
year = {1993},
abstract = {Wilms' tumor is a childhood nephroblastoma that is postulated to arise through the inactivation of a tumor suppressor gene by a two-hit mechanism. A candidate II p 13 Wilms' tumor gene, WTI, has been cloned and shown to encode a zinc finger protein. Patients with the WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) have a high risk of developing Wilms' tumor and they carry constitutional deletions of one chromosome II allele encompassing the WTI gene. Analysis of the remaining WTI allele in a Wilms' tumor from a WAGR patient revealed the deletion of a single nucleotide in exon 7. This mutation likely played a key role in tumor formation, as it prevents translation of the DNA-binding zinc finger domain that is essential for the function of the WTI polypeptide as a transcriptional regulator.},
subject = {Biochemie},
language = {en}
}
@article{SchwarzHameisterGessleretal.1994,
author = {Schwarz, Klaus and Hameister, Horst and Gessler, Manfred and Grzeschik, Karl-Heinz and Hansen-Hagge, Thomas E. and Bartram, Claus R.},
title = {Confirmation of the localization of the human recombination activating gene 1 (RAG1) to chromosome 11p13},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59136},
year = {1994},
abstract = {The human recombination activating gene 1 (RAGl) has previously been mapped to chromosomes 14q and 11 p. Here we confirm the chromosome 11 assignment by two independent approaches: autoradiographic and fluorescence in situ hybridization to metaphase spreads and analysis of human-hamster somatic cell hybrid DNA by the polymerase chain reaction (PCR) and Southern blotting. Our results unequivocally localize RAG1 to llp13.},
subject = {Biochemie},
language = {en}
}
@article{SchwartzNeveEisenmanetal.1994,
author = {Schwartz, Faina and Neve, Rachel and Eisenman, Robert and Gessler, Manfred and Bruns, Gail},
title = {A WAGR region gene between PAX-6 and FSHB expressed in fetal brain},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59125},
year = {1994},
abstract = {Developmental delay or mental retardation is a frequent component of multi-system anomaly syndromes associated with chromosomal deletions. Isolation of genes involved in the mental dysfunction in these disorders should define loci important in brain formation or function. We have identified a highly conserved locus in the distal part of 11 p 13 that is prominently expressed in fetal brain. Minimal expression is observed in a number of other fetal tissues. The gene maps distal to PAX-6 but proximal to the loci for brain-derived neurotrophic factor (BDNF) and the beta subunit of follicle stimulating hormone (FSHB), within a region previously implicated in the mental retardation component of some WAGR syndrome patients. Within fetal brain, the corresponding transcript is prominent in frontal, motor and primary visual cortex as weil as in the caudate-putamen. The characteristics of this gene, including the striking evolutionary conservation at the locus, suggest that the encoded protein may function in brain development.},
subject = {Biochemie},
language = {en}
}
@article{TzagoloffMacinoSebald1979,
author = {Tzagoloff, A. and Macino, G. and Sebald, Walter},
title = {Mitochondrial genes and translation products},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47408},
year = {1979},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{vonJagowSebald1980,
author = {von Jagow, Gerhard and Sebald, Walter},
title = {b-Type cytochromes},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47383},
year = {1980},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@article{HoppeSchairerSebald1980,
author = {Hoppe, J. and Schairer, HU and Sebald, Walter},
title = {Identification of amino-acid substitutions in the proteolipid subunit of the ATP synthase from dicyclohexylcarbodiimide-resistant mutants of Escherichia coli},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47374},
year = {1980},
abstract = {The amino acid sequence of the proteolipid subunit of the A TP synthase was analyzed in six mutant strains from Escherichia coli K 12, selected for their increased resistance towards the inhibitor N,N'-dicyclohexylcarbodiimide. All six inhibitor-resistant mutants were found to be altered at the same position of the proteolipid, namely at the isoleucine at residue 28. Two substitutions could be identified. In type I this residue was substituted by a valine resulting in a moderate decrease in sensitivity to dicyclohexylcarbodiimide. Type II contained a threonine residue at this position. Here a strong resistance was observed. These two amino acid substitutions did not influence functional properties of the ATPase complex. ATPase as well as A TP-dependent proton-translocating activities of mutant membranes were indistinguishable from the wild type. At elevated concentrations, dicyclohexylcarbodiimide still bound specifically to the aspartic acid at residue 61 of the mutant proteolipid as in the wild type, and thereby inhibited the activity of the ATPase complex. It is suggested that the residue 28 substituted in the resistant mutants interacts with dicyclohexylcarbodiimide during the reactions leading to the covalent attachment of the inhibitor to the aspartic acid at residue 61. This could indicate that these two residues are in close vicinity and would thus provide a first hint on the functional conformation of the proteolipid. Its polypeptide chain would have to fold back to bring together these two residues separated by a segment of 32 residues.},
subject = {Biochemie},
language = {en}
}
@article{Sebald1977,
author = {Sebald, Walter},
title = {Biogenesis of mitochondrial ATPase},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47362},
year = {1977},
abstract = {No abstract available},
subject = {Biochemie},
language = {en}
}
@phdthesis{Kraich2008,
author = {Kraich, Michael},
title = {Strukturelle und funktionelle Untersuchungen der Interaktion zwischen Ligand und Rezeptor im Interleukin-4- und Interleukin-13-System},
url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27655},
school = {Universit{\"a}t W{\"u}rzburg},
year = {2008},
abstract = {Interleukin-4 (IL-4) und Interleukin-13 (IL-13) sind bedeutende Regulatorproteine des Immunsystems. Sie spielen eine entscheidende Rolle bei der Entstehung und dem Verlauf von allergischen Erkrankungen, wie z.B. Asthma. Um ihre Signale in die Zielzelle zu transduzieren, kann von beiden Zytokinen der gleiche Zelloberfl{\"a}chenrezeptor verwendet werden, wodurch sich die {\"u}berlappenden, biologischen Funktionen erkl{\"a}ren lassen. Dieser gemeinsam genutzte Rezeptor ist aus den beiden Untereinheiten IL-4Ralpha; und IL-13Ralpha1 aufgebaut. Da IL-4 und IL-13 auf Aminos{\"a}ureebene nur etwa 25\% Sequenzidentit{\"a}t besitzen und stark unterschiedliche Affinit{\"a}ten zu den beiden Rezeptorketten besitzen, stellt sich die Frage, durch welchen molekularen Erkennungsmechanismus, die Affinit{\"a}t und die Spezifit{\"a}t der Ligand-Rezeptor-Interaktion unabh{\"a}ngig voneinander reguliert werden kann. In dieser Arbeit gelang es, rekombinante Expressions- und Aufreinigungsstrategien f{\"u}r IL-13 und die extrazellul{\"a}ren Dom{\"a}nen der Rezeptorketten IL-13Ralpha1 und IL-13Ralpha2 zu entwickeln. Dadurch war es m{\"o}gliche, eine breite Mutations-/Interaktionsanalyse der IL-13Ralpha1-Kette durchzuf{\"u}hren.Es konnte gezeigt werden, dass die N-terminale FnIII-{\"a}hnliche Dom{\"a}ne von IL-13Ralpha1 sowohl an der Bindung von IL-13 als auch an der Interaktion mit IL-4 beteiligt ist. Im funktionellen Bindeepitop der IL-13Ralpha1-Kette wurden die Aminos{\"a}urereste Arg84, Phe253 und Tyr321 als Hauptbindungsdeterminanten f{\"u}r die Interaktion mit IL-13 identifiziert. Durch die Interaktionsstudien der IL-13Ralpha1-Varianten mit IL-4 wurde gezeigt, dass diese Hauptbindungsdeterminanten auch f{\"u}r die niederaffine Bindung von IL-4 von gr{\"o}ßter Bedeutung sind. Die funktionellen Bindeepitope f{\"u}r IL-4 und IL-13 auf der IL-13Ralpha1-Kette sind nahezu identisch und {\"u}berlappen in einem großen Bereich. Aufgrund der Ergebnisse aus der Mutagenesestudie war es m{\"o}glich, ein Strukturmodell der extrazellul{\"a}ren Dom{\"a}ne der IL-13Ralpha1-Kette zu erstellen. Darin wird eine neuartige Orientierung der N-terminalen FnIII-Dom{\"a}ne und deren Beteiligung an der Ligandeninteraktion dargestellt. Mit Hilfe des Strukturmodells gelang es, neue Aminos{\"a}urerest auf der Oberfl{\"a}che von IL-13 zu identifizieren, die an der Bindung zu IL-13Ralpha1 beteiligt sind, was die Relevanz des Strukturmodells weiter unterstreicht. In einem weiteren Teil dieser Arbeit wurde versucht, den molekularen Mechanismus aufzukl{\"a}ren, durch den es den superagonistischen IL-4-Varianten T13D und F82D gelingt, mit dreifach h{\"o}herer Affinit{\"a}t an die IL-4Ralpha-Kette zu binden, als wildtypischer Ligand. Durch strukturelle und funktionelle Untersuchungen wurde gezeigt, dass der Affinit{\"a}tssteigerung ein indirekter Mechanismus zugrunde liegt, bei dem eine Konformations{\"a}nderung und die Fixierung der Arg85-Seitenkette von IL-4 zur Ausbildung von zus{\"a}tzlichen Ligand-Rezeptor-Interaktionen f{\"u}hrt. Das Bindeepitop zwischen IL-4 und der IL-4Ralpha-Kette besitzt eine modulare Architektur aus drei unabh{\"a}ngig voneinander agierenden Interaktionsclustern. Bei der Interaktion von wildtypischem IL-4 mit IL-4Ralpha tragen nur zwei dieser Cluster in signifikanter Weise zur freien Bindeenergie bei. Im Falle der superagonistischen IL-4-Varianten ist jedoch auch das dritte Cluster an der Generierung von zus{\"a}tzlicher, freier Bindeenergie beteiligt, wodurch die Affinit{\"a}t zwischen Ligand und Rezeptor erh{\"o}ht wird. Damit stellt der modulare Aufbau der Interaktionsfl{\"a}che zwischen IL-4 und der IL-4Ralpha-Kette m{\"o}glicherweise einen Mechanismus dar, {\"u}ber den Proteine die Affinit{\"a}t von Wechselwirkungen {\"u}ber einen großen Bereicht variieren k{\"o}nnen, ohne dabei Spezifit{\"a}t einzub{\"u}ssen. Da IL-4 und IL-13 als interessante Zielmolek{\"u}le f{\"u}r die Therapie von allergischen und asthmatischen Erkrankungen erkannt worden sind, k{\"o}nnen die in der vorliegenden Arbeit gewonnenen Informationen {\"u}ber den Bindemechanismus und die Einblicke in den molekularen Charakter der Interaktion zwischen den beiden Zytokinen und ihren spezifischen Rezeptorketten dabei helfen, neuartige und hoch spezifische, inhibitorische Molek{\"u}le zu entwickeln.},
subject = {Renaturierung },
language = {de}
}