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761.
762.
Anne Trefzer Pallavi Kadam Shu-Hung Wang Stefanie Pennavaria Benedikt Lober Batuhan Akçabozan Jan Kranich Thomas Brocker Naoko Nakano Martin Irmler Johannes Beckers Tobias Straub Reinhard Obst 《Cell reports》2021,34(6):108748
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763.
Juliane Kums Johannes Nelke Benedikt Rüth Viktoria Schäfer Daniela Siegmund 《MABS-AUSTIN》2017,9(3):506-520
Cell surface antigen-specific antibodies are of substantial diagnostic and therapeutic importance. The binding properties of such antibodies are usually evaluated by cell-free assays, in particular surface plasmon resonance (SPR) analysis, or flow cytometry. SPR analyses allow the detailed quantitative and dynamic evaluation of the binding properties of antibodies, but need purified, typically recombinantly produced antigens. It can, however, be difficult to produce the required antigen. Furthermore, cellular factors influencing the antigen-antibody interaction are not considered by this method. Flow cytometry-based analyses do not have these limitations, but require elaborated calibration controls for absolute quantification of bound molecules. To overcome the limitations of SRP and flow cytometry in the characterization of cell surface antigen-specific antibodies, we developed Fn14-specific antibody 18D1 as an example of an antibody fusion protein format that includes the luciferase of Gaussia princeps (GpL), which enables very simple and highly sensitive cellular binding studies. We found that GpL-tagging of the C-terminus of the antibody light chain does not affect the interaction of 18D1-IgG1 with its antigen and Fc-gamma receptors (FcγRs). In accordance with this, the GpL(LC-CT)-18D1-IgG1 antibody fusion protein showed basically the same FcγR-dependent agonistic properties as the parental 18D1 antibody. Similar results were obtained with isotype switch variants of 18D1 and antibodies specific for CD95, LTβR and CD40. In sum, we demonstrate that antibody GpL fusion proteins are easily manageable and versatile tools for the characterization of cell surface antigen-antibody interactions that have the potential to considerably extend the instrumentarium for the evaluation of antibodies. 相似文献
764.
Priyank Patel Benedikt Asbach Elina Shteyn Cindy Gomez Alexander Coltoff Sadia Bhuyan Angela L. Tyner Ralf Wagner Stacy W. Blain 《Molecular and cellular biology》2015,35(9):1506-1522
Cyclin D and cyclin-dependent kinase 4 (cdk4) are overexpressed in a variety of tumors, but their levels are not accurate indicators of oncogenic activity because an accessory factor such as p27Kip1 is required to assemble this unstable dimer. Additionally, tyrosine (Y) phosphorylation of p27 (pY88) is required to activate cdk4, acting as an “on/off switch.” We identified two SH3 recruitment domains within p27 that modulate pY88, thereby modulating cdk4 activity. Via an SH3-PXXP interaction screen, we identified Brk (breast tumor-related kinase) as a high-affinity p27 kinase. Modulation of Brk in breast cancer cells modulates pY88 and increases resistance to the cdk4 inhibitor PD 0332991. An alternatively spliced form of Brk (Alt Brk) which contains its SH3 domain blocks pY88 and acts as an endogenous cdk4 inhibitor, identifying a potentially targetable regulatory region within p27. Brk is overexpressed in 60% of breast carcinomas, suggesting that this facilitates cell cycle progression by modulating cdk4 through p27 Y phosphorylation. p27 has been considered a tumor suppressor, but our data strengthen the idea that it should also be considered an oncoprotein, responsible for cyclin D-cdk4 activity. 相似文献
765.
766.
Benedikt Hallgrímsson Heather Jamniczky Nathan M. Young Campbell Rolian Trish E. Parsons Julia C. Boughner Ralph S. Marcucio 《Evolutionary biology》2009,36(4):355-376
Organisms represent a complex arrangement of anatomical structures and individuated parts that must maintain functional associations
through development. This integration of variation between functionally related body parts and the modular organization of
development are fundamental determinants of their evolvability. This is because integration results in the expression of coordinated
variation that can create preferred directions for evolutionary change, while modularity enables variation in a group of traits
or regions to accumulate without deleterious effects on other aspects of the organism. Using our own work on both model systems
(e.g., lab mice, avians) and natural populations of rodents and primates, we explore in this paper the relationship between
patterns of phenotypic covariation and the developmental determinants of integration that those patterns are assumed to reflect.
We show that integration cannot be reliably studied through phenotypic covariance patterns alone and argue that the relationship
between phenotypic covariation and integration is obscured in two ways. One is the superimposition of multiple determinants
of covariance in complex systems and the other is the dependence of covariation structure on variances in covariance-generating
processes. As a consequence, we argue that the direct study of the developmental determinants of integration in model systems
is necessary to fully interpret patterns of covariation in natural populations, to link covariation patterns to the processes
that generate them, and to understand their significance for evolutionary explanation. 相似文献
767.
768.
Heather A. Jamniczky Benedikt Hallgrímsson 《Evolution; international journal of organic evolution》2009,63(6):1540-1556
Mutations have the ability to produce dramatic changes to covariance structure by altering the variance of covariance-generating developmental processes. Several evolutionary mechanisms exist that may be acting interdependently to stabilize covariance structure, despite this developmental potential for variation within species. We explore covariance structure in the crania of laboratory mouse mutants exhibiting mild-to-significant developmental perturbations of the cranium, and contrast it with covariance structure in related wild muroid taxa. Phenotypic covariance structure is conserved among wild muroidea, but highly variable and mutation-dependent within the laboratory group. We show that covariance structures in natural populations of related species occupy a more restricted portion of covariance structure space than do the covariance structures resulting from single mutations of significant effect or the almost nonexistent genetic differences that separate inbred mouse strains. Our results suggest that developmental constraint is not the primary mechanism acting to stabilize covariance structure, and imply a more important role for other mechanisms. 相似文献
769.
770.
Anne Clancy Claire Heride Adn Pinto-Fernndez Hannah Elcocks Andreas Kallinos Katherine J. Kayser-Bricker Weiping Wang Victoria Smith Simon Davis Shawn Fessler Crystal McKinnon Marie Katz Tim Hammonds Neil P. Jones Jonathan OConnell Bruce Follows Steven Mischke Justin A. Caravella Stephanos Ioannidis Christopher Dinsmore Sunkyu Kim Axel Behrens David Komander Benedikt M. Kessler Sylvie Urb Michael J. Clague 《The Journal of cell biology》2021,220(3)
When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. Such an encounter leads to the formation of a stable di-ribosome complex, which needs to be resolved by a dedicated machinery. The initial stalling and the subsequent resolution of di-ribosomal complexes requires activity of Makorin and ZNF598 ubiquitin E3 ligases, respectively, through ubiquitylation of the eS10 and uS10 subunits of the ribosome. We have developed a specific small-molecule inhibitor of the deubiquitylase USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome-associated protein stability but also reveals a loss of Makorin 2 and ZNF598. We show that USP9X interacts with both these ubiquitin E3 ligases, regulating their abundance through the control of protein stability. In the absence of USP9X or following chemical inhibition of its catalytic activity, levels of Makorins and ZNF598 are diminished, and the ribosomal quality control pathway is impaired. 相似文献