PubMed · 4147582
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J F van Reenen. 1973. Microbiologic studies on denture stomatitis.. https://pubmed.ncbi.nlm.nih.gov/4147582/
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In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.
Recent studies in our laboratory have demonstrated that mechanical strain alters many facets of keratinocyte biology including proliferation, protein synthesis, and morphology. IL-1 is known to play an important role in the autocrine regulation of these basic cellular properties under basal and stimulated conditions. However, it is not known whether IL-1 plays a role in strain-induced alteration of keratinocyte biology. Thus, the objective of this study was to test the hypothesis that cyclic strain stimulates IL-1 expression and that strain-induced changes in keratinocyte function is regulated by IL-1. To test this hypothesis, we examined the effect of cyclic strain (10% average deformation) on keratinocyte IL-1 gene expression and the effect of neutralizing antibodies of IL-1 alpha and IL-1 beta on strain-induced changes in keratinocyte proliferation, morphology, and orientation. Northern blot analyses demonstrated that steady state levels of IL-1 alpha and beta mRNA were elevated by 4 h, peaked at 1 2 h of cyclic strain (IL-1 alpha, 304+/-14.2%; IL-1 beta, 212+/-5.6% increase vs. static controls) and decreased gradually by 24 h. IL-1 antibodies (IL-1 alpha, 0.01 microg/ml; IL-1 beta, 0.01 microg/ml) significantly blocked strain-induced keratinocyte proliferation as well as the basal rate of proliferation. In contrast, IL-1 antibodies (IL-1 alpha, 0.01 microg/ml; IL-1 beta, 0.1 microg/ml) had no effect on strain-induced morphological changes such as elongation and alignment. We conclude that mechanical strain induces IL-1 mRNA expression in keratinocytes. The role of IL-1 in mediating strain-induced changes in keratinocyte biology remains to be determined but appears to be independent of morphological changes.
Cellular adhesion through the beta2 integrin lymphocyte function-associated Ag (LFA)-1 is a complex event involving activation, ligand binding, and cell shape changes that ultimately result in enhanced adhesion. In this report we define requirements for ligand binding and post receptor signaling by comparing two mechanisms of activation of LFA-1: 1) inside-out signaling and 2) direct activation by the beta2 Ab, CBR LFA-1/2. Our results demonstrate that activation of LFA-1 binding to ICAM-1 by CBR LFA-1/2, in contrast to inside-out signaling mechanisms, does not require protein kinase C activation or protein phosphatase 2A activity nor is it affected by agents that interfere with reorganization of the cytoskeleton. Inhibition of protein tyrosine kinase activity does not affect ICAM- binding by either mechanism of activation. However, activation by either mode does require the presence of the beta cytoplasmic domain; deletion of the C-terminal phenylalanine or the five amino acid stretch between 756-762 abolished activation of LFA-1. This, combined with the observation that intracellular energy pools must be preserved, implicates the beta cytoplasmic domain in a key energy-dependent conformational change in LFA-1 that is required to achieve enhanced ligand binding. Post ligand binding events induced by both PMA and Ab stimulation, as measured by homotypic aggregation, require protein tyrosine kinase, phosphatase, and RhoA activities. By examining both ligand binding and aggregation, we have been able to dissect the signaling components critical in the multistep process of LFA-1-mediated cellular adhesion.