Negative regulation of ErbB family receptor tyrosine kinases

Receptors of the EGF receptor or ErbB family of growth factor receptor tyrosine kinases are frequently overexpressed in a variety of solid tumours, and the aberrant activation of their tyrosine kinase activities is thought to contribute to tumour growth and progression. Much effort has been put into developing inhibitors of ErbB receptors, and both antibody and small-molecule approaches have exhibited clinical success. Recently, a number of endogenous negative regulatory proteins have been identified that suppress the signalling activity of ErbB receptors in cells. These include intracellular RING finger E3 ubiquitin ligases such as cbl and Nrdp1 that mediate ErbB receptor degradation, and may include a wide variety of secreted and transmembrane proteins that suppress receptor activation by growth factor ligands. It will be of interest to determine the extent to which tumour cells suppress these pathways to promote their progression, and whether restoration of endogenous receptor-negative regulatory pathways may be exploited for therapeutic benefit

Hypermatrix factors for string and membrane junctions

The adjoint representations of the Lie algebras of the classical groups SU(n), SO(n), and Sp(n) are, respectively, tensor, antisymmetric, and symmetric products of two vector spaces, and hence are matrix representations. We consider the analogous products of three vector spaces and study when they appear as summands in Lie algebra decompositions. The Z3-grading of the exceptional Lie algebras provide such summands and provides representations of classical groups on hypermatrices. The main natural application is a formal study of three-junctions of strings and membranes. Generalizations are also considered.Comment: 25 pages, 4 figures, presentation improved, minor correction

The von Hippel-Lindau Tumor Suppressor Protein Promotes c-Cbl-Independent Poly-Ubiquitylation and Degradation of the Activated EGFR

Somatic mutations or reduced expression of the von Hippel-Lindau (VHL) tumor suppressor occurs in the majority of the clear cell renal cell carcinoma (ccRCC) and is a causal factor for the pathogenesis of ccRCC. pVHL was reported to suppress the oncogenic activity of Epidermal Growth Factor Receptor (EGFR) by reducing the expression of the EGFR agonist TGF-α and by reducing the translation efficiency of EGFR itself. Furthermore, it was reported that pVHL down-regulates activated EGFR by promoting efficient lysosomal degradation of the receptor. These modes of negative regulation of EGFR by pVHL were dependent on Hypoxia Inducible Factor (HIF). In this study, we report that HIF was not the only factor stabilizing the activated EGFR in VHL-deficient ccRCC cells. Down-regulation of endogenous HIF in these cells had little effect on the turnover rates of the activated EGFR. Furthermore, neither pretreatment with lysomomal inhibitors pretreatment nor down-regulation of c-Cbl, a major E3 ubiquitin ligase that targets the activated EGFR for lysosomal degradation, significantly increased the stabilities of EGFR in VHL-expressing ccRCC cells. In contrast, pretreatment with proteasomal inhibitors extended EGFR lifetime and led to similar EGFR half-lives in VHL-expressing and VHL-deficient ccRCC cells. Down-regulation of c-Cbl in VHL-deficient ccRCC cells revealed that the c-Cbl and pVHL collaborated to down-regulate the activated EGFR. Finally, we found that pVHL promoted the poly-ubiquitylation of the activated EGFR, and this function was c-Cbl-independent. Thus these results indicate that pVHL limits EGFR signaling by promoting c-Cbl-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome

Automatic volumetry on MR brain images can support diagnostic decision making.

Background: Diagnostic decisions in clinical imaging currently rely almost exclusively on visual image interpretation. This can lead to uncertainty, for example in dementia disease, where some of the changes resemble those of normal ageing. We hypothesized that extracting volumetric data from patients MR brain images, relating them to reference data and presenting the results as a colour overlay on the grey scale data would aid diagnostic readers in classifying dementia disease versus normal ageing. Methods: A proof-of-concept forced-choice reader study was designed using MR brain images from 36 subjects. Images were segmented into 43 regions using an automatic atlas registration-based label propagation procedure. Seven subjects had clinically probable AD, the remaining 29 of a similar age range were used as controls. Seven of the control subject data sets were selected at random to be presented along with the seven AD datasets to two readers, who were blinded to all clinical and demographic information except age and gender. Readers were asked to review the grey scale MR images and to record their choice of diagnosis (AD or non-AD) along with their confidence in this decision. Afterwards, readers were given the option to switch on a false-colour overlay representing the relative size of the segmented structures. Colorization was based on the size rank of the test subject when compared with a reference group consisting of the 22 control subjects who were not used as review subjects. The readers were then asked to record whether and how the additional information had an impact on their diagnostic confidence. Results: The size rank colour overlays were useful in 18 of 28 diagnoses, as determined by their impact on readers diagnostic confidence. A not useful result was found in 6 of 28 cases. The impact of the additional information on diagnostic confidence was significant (p < 0.02). Conclusion: Volumetric anatomical information extracted from brain images using automatic segmentation and presented as colour overlays can support diagnostic decision making. © 2008 Heckemann et al; licensee BioMed Central Ltd.Published versio

An Excellent Monitoring System for Surface Ubiquitination-Induced Internalization in Mammals

Background. At present, it is difficult to visualize the internalization of surface receptors induced by ubiquitination that is taken place at the plasma membrane in mammals. This problem makes it difficult to reveal molecular basis for ubiquitinationmediated internalization in mammals. Methodology/Principle Findings. In order to overcome it, we have generated T-REx-c-MIR, a novel mammalian Tet-on B cell line using a constitutively active E3 ubiquitin ligase, c-MIR, and its artificial target molecule. By applying the surface biotinylation method to T-REx-c-MIR, we succeeded to monitor the fate of surface target molecules after initiation of ubiquitination process by doxycycline (Dox)-induced c-MIR expression. Target molecules that preexisted at the plasma membrane before induction of c-MIR expression were oligo-ubiquitinated and degraded by Dox-induced c-MIR expression. Dox-induced c-MIR expression initiated rapid internalization of surface target molecules, and blockage of the internalization induced the accumulation of the surface target molecules that were newly ubiquitinated by c-MIR. Inhibition of the surface ubiquitination by down-regulating ubiquitin conjugating enzyme E2 impaired the internalization of target molecules. Finally, a complex of c-MIR and target molecule was detected at the plasma membrane. Conclusions/ Significances. These results demonstrate that in T-REx-c-MIR, surface target molecule is ubiquitinated at the plasma membrane and followed by being internalized from the plasma membrane. Thus, T-REx-c-MIR is a useful experimental tool t

Computing and visually analyzing mutual information in molecular co-evolution

<p>Abstract</p> <p>Background</p> <p>Selective pressure in molecular evolution leads to uneven distributions of amino acids and nucleotides. In fact one observes correlations among such constituents due to a large number of biophysical mechanisms (folding properties, electrostatics, ...). To quantify these correlations the mutual information -after proper normalization - has proven most effective. The challenge is to navigate the large amount of data, which in a study for a typical protein cannot simply be plotted.</p> <p>Results</p> <p>To visually analyze mutual information we developed a matrix visualization tool that allows different views on the mutual information matrix: filtering, sorting, and weighting are among them. The user can interactively navigate a huge matrix in real-time and search e.g., for patterns and unusual high or low values. A computation of the mutual information matrix for a sequence alignment in FASTA-format is possible. The respective stand-alone program computes in addition proper normalizations for a null model of neutral evolution and maps the mutual information to <it>Z</it>-scores with respect to the null model.</p> <p>Conclusions</p> <p>The new tool allows to compute and visually analyze sequence data for possible co-evolutionary signals. The tool has already been successfully employed in evolutionary studies on HIV1 protease and acetylcholinesterase. The functionality of the tool was defined by users using the tool in real-world research. The software can also be used for visual analysis of other matrix-like data, such as information obtained by DNA microarray experiments. The package is platform-independently implemented in <monospace>Java</monospace> and free for academic use under a GPL license.</p

Lesion detection in demoscopy images with novel density-based and active contour approaches

<p>Abstract</p> <p>Background</p> <p>Dermoscopy is one of the major imaging modalities used in the diagnosis of melanoma and other pigmented skin lesions. Automated assessment tools for dermoscopy images have become an important field of research mainly because of inter- and intra-observer variations in human interpretation. One of the most important steps in dermoscopy image analysis is the detection of lesion borders, since many other features, such as asymmetry, border irregularity, and abrupt border cutoff, rely on the boundary of the lesion. </p> <p>Results</p> <p>To automate the process of delineating the lesions, we employed Active Contour Model (ACM) and boundary-driven density-based clustering (BD-DBSCAN) algorithms on 50 dermoscopy images, which also have ground truths to be used for quantitative comparison. We have observed that ACM and BD-DBSCAN have the same border error of 6.6% on all images. To address noisy images, BD-DBSCAN can perform better delineation than ACM. However, when used with optimum parameters, ACM outperforms BD-DBSCAN, since ACM has a higher recall ratio.</p> <p>Conclusion</p> <p>We successfully proposed two new frameworks to delineate suspicious lesions with i) an ACM integrated approach with sharpening and ii) a fast boundary-driven density-based clustering technique. ACM shrinks a curve toward the boundary of the lesion. To guide the evolution, the model employs the exact solution <abbrgrp><abbr bid="B27">27</abbr></abbrgrp> of a specific form of the Geometric Heat Partial Differential Equation <abbrgrp><abbr bid="B28">28</abbr></abbrgrp>. To make ACM advance through noisy images, an improvement of the model’s boundary condition is under consideration. BD-DBSCAN improves regular density-based algorithm to select query points intelligently.</p

Acquired resistance to anti-EGFR mAb ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers

Our results provide a novel mechanistic insight into the development of acquired resistance to EGFR antibody-based therapy in colorectal cancer cells and justify further investigations on the therapeutic benefits of pan-HER family inhibitors in the treatment of colorectal cancer patients once acquired resistance to EGFR antibody-based therapy is developed

The role of the ubiquitination–proteasome pathway in breast cancer: Ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer

Aberrant activity of growth factor receptors has been implicated in the pathogenesis of a wide variety of malignancies. The negative regulation of signaling by growth factor receptors is mediated in large part by the ubiquitination, internalization, and degradation of the activated receptor. Over the past few years, considerable insight into the mechanisms that control receptor downregulation has been gained. There are also data suggesting that mutations that lead to inhibition of downregulation of growth factor receptors could play a role in the pathogenesis of cancer. Therapies directed at enhancing the degradation of growth factor receptors offer a promising approach to the treatment of malignancies