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Molecular Requirements (molecular + requirement)
Selected AbstractsEpidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5a 2008Michael Vibo Grandal ,,Introduction ,,Endocytosis of EGFR -,Kinase activity -,Clathrin-coated pits -,Ubiquitination -,Effects of EGFR-ErbB2 heterodimerization on EGFR internalization ,,Cellular and molecular requirements for lysosomal degradation of EGFR -,Intracellular EGFR degradation depends on luminal sorting at multivesicular bodies -,Molecular requirements for EGFR sorting in multivesicular endosomes Abstract The epidermal growth factor receptor (EGFR) and other members of the EGFR/ErbB receptor family of receptor tyrosine kinases (RTKs) are important regulators of proliferation, angiogenesis, migration, tumorigenesis and metastasis. Overexpression, mutations, deletions and production of autocrine ligands contribute to aberrant activation of the ErbB proteins. The signalling output from EGFR is complicated given that other ErbB proteins are often additionally expressed and activated in the same cell, resulting in formation of homo-and/or heterodimers. In particular, association of EGFR with ErbB2 prevents its down-regulation, underscoring the importance of the cellular background for EGFR effects. Signalling from ErbB proteins can either be terminated by dissociation of ligand resulting in dephosphorylation, or blunted by degradation of the receptors. Although proteasomal targeting of ErbB proteins has been described, lysosomal degradation upon ligand-induced endocytosis seems to play the major role in EGFR down-regulation. Preclinical and clinical data have demonstrated that EGFR is a central player in cancer, especially in carcinomas, some brain tumours and in non-small cell lung cancer. Such studies have further validated EGFR as an important molecular target in cancer treatment. This review focuses on mechanisms involved in ligand-induced EGFR activation and endocytic down-regulation. A better understanding of EGFR biology should allow development of more tumour-selective therapeutic approaches targeting EGFR-induced signalling. [source] Neutrophils in a mouse model of autoantibody-mediated arthritis: Critical producers of Fc receptor ,, the receptor for C5a, and lymphocyte function,associated antigen 1ARTHRITIS & RHEUMATISM, Issue 3 2010Paul A. Monach Objective Neutrophils represent a prominent component of inflammatory joint effusions and are required for synovial inflammation in mouse models, but the mechanisms are poorly understood. In this study, we developed a system with which to test the importance of the production of specific factors by neutrophils in a mouse model of arthritis. Methods Neutrophil-deficient Gfi-1,/, mice were administered sublethal doses of radiation and were then engrafted with donor bone marrow cells (BMCs), which resulted in the production of mature neutrophils within 2 weeks. By reconstituting with BMCs from mice lacking selected proinflammatory factors, we generated mice that specifically lacked these factors on their neutrophils. Arthritis was initiated by transfer of K/BxN serum to identify the role of defined neutrophil factors on the incidence and severity of arthritis. Results Neutrophils lacking the signaling chain of stimulatory Fc receptors (FcR,,/,) were unable to elicit arthritis, but neutrophils lacking Fc,RIII still did so. Neutrophils lacking the chemotactic or adhesion receptor C5a receptor (C5aR) or CD11a/lymphocyte function,associated antigen 1 (LFA-1) also failed to initiate arthritis but could enter joints in which inflammation had been initiated by wild-type neutrophils. Neutrophils unable to produce interleukin-1, (IL-1,) and IL-1, (IL-1,/,,/,) or leukotrienes (5-lipoxygenase [5-LOX,/,]) produced arthritis of intermediate severity. The inability of neutrophils to make tumor necrosis factor or to express receptors for tumor necrosis factor or IL-1 had no effect on arthritis. Conclusion A novel transfer system was developed to identify neutrophil production of FcR,, C5aR, and CD11a/LFA-1 as critical components of autoantibody-mediated arthritis. Neutrophil production of IL-1 and leukotriene B4 likely contributes to inflammation but is not essential. Molecular requirements for neutrophil influx into joints become more permissive after inflammation is initiated. [source] Novel mechanism of blocking axonal Na+ channels by three macrocyclic polyamine analogues and two spider toxinsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2001Masuhide Yakehiro The mechanism of Na+ channel block by three macrocyclic polyamine derivatives and two spider toxins was studied with voltage clamp and internal perfusion method in squid axons. All these chemicals specifically block Na+ channels in the open state only from the internal surface, and do not affect K+ channels. The blocking effect is enhanced as the depolarizing pulse becomes larger. Blocked channels are unable to shift to the inactivated state. In the case of cyclam and guanidyl-side armed cyclam (G-cyclam), quick release of these chemicals from the binding sites is proven by the increase in the tail current and prolongation of the time course of the off gating current. On the other hand, in the presence of N-4 and the spider toxins, their detachment was delayed significantly. Molecular requirements for the block of Na+ channels by these molecules are the presence of positive charge and hydrophobicity. British Journal of Pharmacology (2001) 132, 63,72; doi:10.1038/sj.bjp.0703765 [source] Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular inputEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2008Andrea Abstract Intrathymic deletion of immature thymocytes that express self-reactive TCR specificities is essential in the generation of self tolerance. Medullary thymic epithelial cells (mTEC) expressing the transcriptional regulator Aire play a key role in this process by regulating expression of tissue-restricted antigens to ensure tolerance to peripheral tissues. Here, we have analysed the cellular and molecular requirements for the initial appearance of Aire+ mTEC in the embryonic thymus, in addition to their persistence in the adult thymus. Analysis of thymic ontogeny shows that the emergence of embryonic Aire+ mTEC occurs prior to the appearance of mature thymocytes, and depends upon lymphoid tissue inducer cells expressing retinoic acid receptor-related orphan receptor,,. In the adult thymus, we show that Aire+ mTEC develop in the absence of thymocyte positive and negative selection and CD40 signalling, but are present at reduced frequency. Collectively these data support a model where the initial differentiation of Aire+ mTEC involves receptor activator of NF-,B (RANK)-RANKL interactions with lymphoid tissue inducer cells, with subsequent mTEC turnover and/or survival involving CD40-mediated signalling following interactions with mature CD4+ thymocytes that express CD40L. [source] Epidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5a 2008Michael Vibo Grandal ,,Introduction ,,Endocytosis of EGFR -,Kinase activity -,Clathrin-coated pits -,Ubiquitination -,Effects of EGFR-ErbB2 heterodimerization on EGFR internalization ,,Cellular and molecular requirements for lysosomal degradation of EGFR -,Intracellular EGFR degradation depends on luminal sorting at multivesicular bodies -,Molecular requirements for EGFR sorting in multivesicular endosomes Abstract The epidermal growth factor receptor (EGFR) and other members of the EGFR/ErbB receptor family of receptor tyrosine kinases (RTKs) are important regulators of proliferation, angiogenesis, migration, tumorigenesis and metastasis. Overexpression, mutations, deletions and production of autocrine ligands contribute to aberrant activation of the ErbB proteins. The signalling output from EGFR is complicated given that other ErbB proteins are often additionally expressed and activated in the same cell, resulting in formation of homo-and/or heterodimers. In particular, association of EGFR with ErbB2 prevents its down-regulation, underscoring the importance of the cellular background for EGFR effects. Signalling from ErbB proteins can either be terminated by dissociation of ligand resulting in dephosphorylation, or blunted by degradation of the receptors. Although proteasomal targeting of ErbB proteins has been described, lysosomal degradation upon ligand-induced endocytosis seems to play the major role in EGFR down-regulation. Preclinical and clinical data have demonstrated that EGFR is a central player in cancer, especially in carcinomas, some brain tumours and in non-small cell lung cancer. Such studies have further validated EGFR as an important molecular target in cancer treatment. This review focuses on mechanisms involved in ligand-induced EGFR activation and endocytic down-regulation. A better understanding of EGFR biology should allow development of more tumour-selective therapeutic approaches targeting EGFR-induced signalling. [source] What an epigenome remembersBIOESSAYS, Issue 8 2010Ulrike C. Lange Abstract During mammalian development, maintenance of cell fate through mitotic divisions require faithful replication not only of the DNA but also of a particular epigenetic state. Germline cells have the capacity of erasing this epigenetic memory at crucial times during development, thereby resetting their epigenome. Certain marks, however, appear to escape this reprogramming, which allows their transmission to the offspring and potentially guarantees transgenerational epigenetic inheritance. Here we discuss the molecular requirements for faithful transmission of epigenetic information and our current knowledge about the transmission of epigenetic information through generations. [source] | ||||||||||