Searching for the physiological role and therapeutic potential of vascular proteinase-activated receptor-2 (PAR2)

Abstract Cells rely on stress response pathways to uphold cellular homeostasis and limit the negative effects of harmful environmental stimuli. The stress- and mitogen-activated protein (MAP) kinases, p38 and JNK, are at the nexus of numerous stress responses, among these the ribotoxic stress response (RSR). Ribosomal impairment is detrimental to cell function as it disrupts protein synthesis, increase inflammatory signaling and, if unresolved, lead to cell death. In this review, we offer a general overview of the three main translation surveillance pathways; the RSR, Ribosome-associated Quality Control (RQC) and the Integrated Stress Response (ISR). We highlight recent advances made in defining activation mechanisms for these pathways and discuss their commonalities and differences. Finally, we reflect on the physiological role of the RSR and consider the therapeutic potential of targeting the sensing kinase ZAKα for treatment of ribotoxin exposure.

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A high-content screen profiles cytotoxic microRNAs in pediatric and adult glioblastoma cells and identifies miR-1300 as a potent inducer of cytokinesis failure

10.1101/789438 ◽

2019 ◽

Author(s):

Marjorie Boissinot ◽

Henry King ◽

Matthew Adams ◽

Julie Higgins ◽

Thomas A. Ward ◽

...

Keyword(s):

Therapeutic Potential ◽

Ectopic Expression ◽

Physiological Role ◽

Mrna Translation ◽

Glioblastoma Cells ◽

Potent Inducer ◽

Functional Studies ◽

Key Points ◽

Megakaryocyte Differentiation

AbstractBackgroundMicroRNAs play an important role in the regulation of mRNA translation, and have therapeutic potential in cancer and other diseases.MethodsTo profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen using a synthetic oligonucleotide library representing all known human microRNAs in adult and pediatric GBM cells. Bio-informatics analysis were used to refine this list and the top seven microRNAs were validated in a larger panel of cells by flow-cytometry, and RTqPCR. The downstream mechanism of the strongest and most consistent candidate was investigated by siRNAs, 3’UTR luciferase assays and Western Blotting.ResultsOur screen identified ∼100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 expressing cells and characterized the mechanism of action as cytokinesis failure followed by apoptosis, which was observed in an extended GBM cell panel including two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In glioblastoma cells, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target of miR-1300. ECT2 siRNA phenocopied the effects of miR-1300, and its overexpression led to a significant rescue of miR-1300 induced binucleation.ConclusionMiR-1300 was identified as a novel regulator of endomitosis with translatable potential for therapeutic application. The datatasets will be a resource for the neuro-oncology community.Key points (2 or 3 key points 85 characters plus spaces each)70% of cytotoxic microRNAs were shared between adult and pediatric glioblastoma cellsMiR-1300 expression is restricted to endomitosis within megakaryocyte differentiationMiR-1300’s ectopic expression is a potent and promising therapeutic tool in cancerImportance of StudyPrevious functional studies of microRNAs involved in the regulation of glioblastoma cell proliferation and/or survival have focused on adult glioblastoma alone and are restricted to only a few microRNAs at a time. Our study provides the first encompassing landscape of potent cytotoxic microRNAs in pediatric and adult glioblastoma.Not only, does our data provide an invaluable resource for the research community but it also revealed that 70% of microRNAs with significant cytotoxicity were shared by adult and pediatric cells. Finally, we identified and characterized the previously undescribed role of microRNA-1300 in the tight regulation of megakaryocyte differentiation into platelets and how, when expressed outside of this context, miR-1300 consistently causes cytokinesis failure followed by apoptosis, and thus represents a powerful cytotoxic tool with potential for translation towards therapeutic applications.

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The regulation of phoenixin: A fascinating multidimensional peptide

Journal of the Endocrine Society ◽

10.1210/jendso/bvab192 ◽

2021 ◽

Author(s):

Emma K McIlwraith ◽

Ningtong Zhang ◽

Denise D Belsham

Keyword(s):

Food Intake ◽

Transcriptional Control ◽

Therapeutic Potential ◽

Physiological Role ◽

Reproductive Hormones ◽

Main Function ◽

Negative Results ◽

Gene And Protein Expression ◽

Its Gene ◽

Range Of Functions

Abstract The phoenixin (PNX) peptide is linked to the control of reproduction, food intake, stress and inflammation. However, little is known about what regulates its gene and protein expression, information that is critical to understand the physiological role of PNX. In this review, we summarize what is known about the transcriptional control of Pnx and its receptor Gpr173. A main function of PNX is as a positive regulator of the hypothalamic-pituitary-gonadal axis, but there is a lack of research on its control by reproductive hormones and peptides. PNX is also associated with food intake and its expression is linked to feeding status, fatty acids, and glucose. It is influenced by environmental and hormonal-induced stress. The regulation of Pnx in most contexts remains an enigma, in part due to conflicting and negative results. An extensive analysis of the response of the Pnx gene to factors related to reproduction, metabolism, stress and inflammation is required. Analysis of the Pnx promoter and epigenetic regulation must be considered to understand how this level of control contributes to its pleiotropic effects. PNX is now linked to a broad range of functions, but more research on its gene regulation is required to understand its place in overall physiology and therapeutic potential.

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M-CSF Inhibition Selectively Targets Tumor Angiogenesis and Lymphangiogenesis

Blood ◽

10.1182/blood.v112.11.1256.1256 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1256-1256

Author(s):

Yoshiaki Kubota ◽

Toshio Suda

Keyword(s):

Tumor Angiogenesis ◽

Therapeutic Potential ◽

Physiological Role ◽

Osteosarcoma Cell ◽

Angiogenic Therapy ◽

High Dependency ◽

Lymphatic Development ◽

Vegf Pathway ◽

Vessel Network ◽

Macrophage Colony

Abstract Anti-angiogenic therapy in cancer is desired to be selective for tumor angiogenesis. The best validated approaches for limiting tumor angiogenesis involve blockade of the VEGF pathway. However, recent studies show that VEGF blockade damages healthy vessels resulting in toxic side effects (Maharaj et al. J. Exp. Med. 2008) and that interrupting the VEGF blockade induces rapid vascular regrowth in tumors (Mancuso et al. J. Clin. Invest. 2006). Therefore, other targets are currently being explored. Macrophage-colony stimulating factor (M-CSF), a cytokine required for differentiation of monocyte-lineage cells including macrophages promotes formation of a high-density vessel network in tumors suggesting therapeutic potential of M-CSF inhibition (Lin et al. J. Exp. Med. 2001). Moreover, M-CSF is abundantly expressed in highly-metastatic cancers such as breast cancer and osteosarcoma, suggesting high dependency on macrophages. However, the physiological role of M-CSF in vascular and lymphatic development as well as the precise mechanisms underlying anti-angiogenic effects of M-CSF inhibition is not clarified. Here, utilizing osteopetrotic (op/op) mice, we show that M-CSF deficiency leads to lack of both LYVE-1+ and LYVE1− macrophages, resulting in defects not only in vascular but also lymphatic development. To clarify the anti-cancer effects of M-CSF inhibition, we utilized a novel mouse model of osteosarcoma, in which mice were transplanted with a newly established osteosarcoma cell line, AX, which were developed from c-Myc-overexpressing Ink4a/ARF−/− bone marrow-derived stromal cells. In this model, systemic treatment with small molecule c-fms inhibitors (Ki20227) effectively suppressed tumor angiogenesis and lymphangiogenesis disorganizing extracellular matrices. Consequently, c-fms inhibitors almost completely suppressed tumor metastasis, and protected mice from cancer death. Different from VEGF blockade, interruption of M-CSF inhibition did not promote rapid tumor regrowth. Continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside the tumor. These results suggest M-CSF-targeted therapy is an ideal therapeutic strategy against cancer alternative to VEGF blockade.

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Self-peptide/MHC and TCR antagonism: Physiological role and therapeutic potential

Cellular Immunology ◽

10.1016/j.cellimm.2005.04.011 ◽

2005 ◽

Vol 233 (2) ◽

pp. 75-84 ◽

Cited By ~ 5

Author(s):

Stanislav Vukmanović ◽

Fabio R. Santori

Keyword(s):

Therapeutic Potential ◽

Physiological Role

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M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis

Journal of Experimental Medicine ◽

10.1084/jem.20081605 ◽

2009 ◽

Vol 206 (5) ◽

pp. 1089-1102 ◽

Cited By ~ 235

Author(s):

Yoshiaki Kubota ◽

Keiyo Takubo ◽

Takatsune Shimizu ◽

Hiroaki Ohno ◽

Kazuo Kishi ◽

...

Keyword(s):

Therapeutic Potential ◽

Antiangiogenic Therapy ◽

Physiological Role ◽

Pathological Angiogenesis ◽

Ischemic Retinopathy ◽

Lymphatic Development ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Vessel Networks

Antiangiogenic therapy for the treatment of cancer and other neovascular diseases is desired to be selective for pathological angiogenesis and lymphangiogenesis. Macrophage colony-stimulating factor (M-CSF), a cytokine required for the differentiation of monocyte lineage cells, promotes the formation of high-density vessel networks in tumors and therefore possesses therapeutic potential as an M-CSF inhibitor. However, the physiological role of M-CSF in vascular and lymphatic development, as well as the precise mechanisms underlying the antiangiogenic effects of M-CSF inhibition, remains unclear. Moreover, therapeutic potential of M-CSF inhibition in other neovascular diseases has not yet been evaluated. We used osteopetrotic (op/op) mice to demonstrate that M-CSF deficiency reduces the abundance of LYVE-1+ and LYVE1− macrophages, resulting in defects in vascular and lymphatic development. In ischemic retinopathy, M-CSF was required for pathological neovascularization but was not required for the recovery of normal vasculature. In mouse osteosarcoma, M-CSF inhibition effectively suppressed tumor angiogenesis and lymphangiogenesis, and it disorganized extracellular matrices. In contrast to VEGF blockade, interruption of M-CSF inhibition did not promote rapid vascular regrowth. Continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside tumors. These results suggest that M-CSF–targeted therapy is an ideal strategy for treating ocular neovascular diseases and cancer.

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Altered GABA Signaling in Early Life Epilepsies

Neural Plasticity ◽

10.1155/2011/527605 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 43

Author(s):

Stephen W. Briggs ◽

Aristea S. Galanopoulou

Keyword(s):

Brain Function ◽

Therapeutic Potential ◽

Physiological Role ◽

Neuronal Morphology ◽

Normal Brain ◽

Pathological Conditions ◽

Neurodevelopmental Deficits ◽

The Brain ◽

Normal Brain Development

The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAAsignaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAAreceptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAAsignaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

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