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Ellegaard Sigmon posted an update 6 months, 2 weeks ago
Our aim is to stimulate an open and accessible discourse in the literature to address issues of continuity across behavioral neurosciences.ErbB3, a member of the ErbB receptor family, is a potent mediator in the development and progression of cancer, and its activation plays pivotal roles in acquired resistance against anti-EGFR therapies and other standard-of-care therapies. Upon ligand (NRG1) binding, ErbB3 forms heterodimers with other ErbB proteins (i.e., EGFR and ErbB2), which allows activation of downstream PI3K/Akt signaling. In this study, we developed a fully human anti-ErbB3 antibody, named ISU104, as an anticancer agent. ISU104 binds potently and specifically to the domain 3 of ErbB3. The complex structure of ErbB3-domain 3ISU104-Fab revealed that ISU104 binds to the NRG1 binding region of domain 3. selleck compound The elucidated structure suggested that the binding of ISU104 to ErbB3 would hinder not only ligand binding but also the structural changes required for heterodimerization. Biochemical studies confirmed these predictions. ISU104 inhibited ligand binding, ligand-dependent heterodimerization and phosphorylation, and induced the internalization of ErbB3. As a result, downstream Akt phosphorylation and cell proliferation were inhibited. The anticancer efficacy of ISU104 was demonstrated in xenograft models of various cancers. In summary, a highly potent ErbB3 targeting antibody, ISU104, is suitable for clinical development.Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer-related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of colorectal cancer cells. MNX1-AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1-AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1-AS1. In addition, MYC bound the promoter of the MNX1-AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1-AS1, which suppressed the proliferation of colorectal cancer cells in both cell-based and patient-derived xenograft models. Collectively, these findings suggest that the MYC-MNX1-AS1-YB1 axis might serve as a potential biomarker and therapeutic target in colorectal cancer. SIGNIFICANCE This study highlights the discovery of a novel colorectal cancer biomarker and therapeutic target, MNX1-AS1, a long noncoding RNA that drives proliferation via a MYC/MNX1-AS1/YB1 signaling pathway. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/10/2636/F1.large.jpg.Germline POT1 mutations are found in a spectrum of cancers and confer increased risk. Recently, we identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. Despite these strong associations, how these glioma-associated POT1 mutations contribute to glioma tumorigenesis remains undefined. Here we show that POT1-G95C increases proliferation in glioma-initiating cells in vitro and in progenitor populations in the developing brain. In a native mouse model of glioma, loss of Pot1a/b resulted in decreased survival in females compared with males. These findings were corroborated in human glioma, where low POT1 expression correlated with decreased survival in females. Transcriptomic and IHC profiling of Pot1a/b-deficient glioma revealed that tumors in females exhibited decreased expression of immune markers and increased expression of cell-cycle signatures. Similar sex-dependent trends were observed in human gliomas that had low expression of POT1. Together, our studies demonstrate context-dependent functions for POT1 mutation or loss in driving progenitor proliferation in the developing brain and sexual dimorphism in glioma. SIGNIFICANCE This study shows that manipulation of POT1 expression in glioma has sex-specific effects on tumorigenesis and associated immune signatures.Bulk loading of neurons with fluorescent calcium indicators in transparent albino Xenopus tadpoles offers a rapid and easy method for tracking sensory-evoked activity in large numbers of neurons within an awake developing brain circuit. In vivo two-photon time-lapse imaging of an image plane through the optic tectum allows defining receptive field properties from visual-evoked responses for studies of single-neuron and network-level encoding and plasticity. Here, we describe loading the Xenopus tadpole optic tectum with the membrane-permeable AM ester of Oregon Green 488 BAPTA-1 (OGB-1 AM) for in vivo imaging experiments.Problems of cell biology and the molecular controls underpinning them have been studied in the remarkably versatile Xenopus systems for many years. This versatility is showcased in several accompanying protocols, which are introduced here. One protocol demonstrates how the Xenopus embryonic ectoderm can be used to study the effects of mechanical cell deformation; another illustrates how the developing eye can be used as a platform for determining cell-cycle length. Two protocols show how extracts from Xenopus embryos can be exploited to characterize the behavior of specific intracellular proteins-specifically, to determine protein phosphorylation status and the ability to bind to chromatin. Finally, because specific antibodies to Xenopus proteins are pivotal reagents for cell biology and biochemistry applications, four protocols describing how to generate, purify, and assay the specificity of antibodies raised against Xenopus proteins are included in hopes of stimulating the expansion of these critical resources across the Xenopus community.
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