scholarly journals Purinergic receptor P2RY14 cAMP signaling regulates EGFR-driven Schwann cell precursor self-renewal and nerve tumor initiation in neurofibromatosis.

2021 ◽  
Author(s):  
Jennifer Patritti-Cram ◽  
Jianqiang Wu ◽  
Shinji Kuninaka ◽  
Robert A Coover ◽  
Robert F Hennigan ◽  
...  
Keyword(s):  
Purinergic Receptor ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Camp Signaling ◽  
Ras Signaling ◽  
Nerve Sheath Tumor ◽  
Self Renewal ◽  
Nerve Tumor

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) lack NF1 and show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. Gene expression profiling and protein expression identified P2RY14 in SCs and SC precursors (SCPs) implicating P2RY14 as a candidate upstream regulator of cAMP in EGF-dependent SCP. We found that SCP self-renewal was reduced by genetic or pharmacological inhibition of P2RY14. In NF1 deficient SCs and malignant peripheral nerve sheath tumor (MPNST) cells, P2RY14 inhibition decreased EGFR-driven phospho-Akt and increased cAMP signaling. In a neurofibroma mouse model, genetic deletion of P2RY14 increased mouse survival, delayed neurofibroma initiation and rescued cAMP signaling. Conversely, elevation of cAMP diminished SCP number in vitro and diminished SC proliferation in neurofibroma bearing mice in vivo. These studies identify the purinergic receptor P2RY14 as a critical G-protein-coupled receptor (GPCR) in NF1 mutant SCPs and SCs and suggest roles for EGFR-GPCR crosstalk in facilitating SCP self-renewal and neurofibroma initiation via cAMP and EGFR-driven phospho-Akt.

scholarly journals STEM-29. THE HISTONE VARIANT macroH2A2 ORCHESTRATES AN ACTIONABLE CHROMATIN PROGRAM OF STEMNESS IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii202-ii202
Author(s):  
Ana Nikolic ◽  
Anna Bobyn ◽  
Katrina Ellestad ◽  
Xueqing Lun ◽  
Michael Johnston ◽  
...  
Keyword(s):  
Chromatin Accessibility ◽  
Histone Variant ◽  
Clinical Settings ◽  
Glioblastoma Cells ◽  
Self Renewal ◽  
Viral Mimicry ◽  
Experimental Findings ◽  
Preclinical Work

Abstract Glioblastoma cells with the crucial stemness property of self-renewal constitute therapy-resistant reservoirs that seed tumor relapse. Effective targeting of these cells in clinical settings has been hampered by their relative quiescence, which invalidates the cell replication bias of most current treatments. Furthermore, although their dependence on specific chromatin and transcriptional states for the maintenance of stemness programs has been proposed as a vulnerability, these nuclear programs have been challenging to target pharmaceutically. Therefore the identification of targetable chromatin paradigms regulating self-renewal would represent a significant advancement for this incurable malignancy. Here we report a new role for the histone variant macroH2A2 in modulating a targetable epigenetic network of stemness in glioblastoma. By integrating transcriptomic, bulk and single-cell epigenomic datasets we generated from patient-derived models and surgical specimens, we show that macroH2A2 represses a transcriptional network of stemness through direct regulation of chromatin accessibility at enhancer elements. Functional assays in vitro and in vivo further showcase that macroH2A2 antagonizes self-renewal and stemness in glioblastoma preclinical models. In agreement with our experimental findings, high expression of macroH2A2 is a positive prognostic factor in clinical glioblastoma cohorts. Reasoning that increasing macroH2A2 levels could be an effective strategy to repress stemness programs and ameliorate patient outcome, we embarked on a screen to identify compounds that could elevate macroH2A2 levels. We report that an inhibitor of the chromatin remodeler Menin increases macroH2A2 levels, which in turn repress self-renewal. Additionally, we provide evidence that Menin inhibition induces viral mimicry programs and the demise of glioblastoma cells. Menin inhibition is being tested in clinical trials for blood malignancies (NCT04067336). Our preclinical work therefore reveals a novel and central role for macroH2A2 in an epigenetic network of stemness and suggests new clinical approaches for glioblastoma.

scholarly journals UV-induced Hyperphosphorylation of Replication Protein A Depends on DNA Replication and Expression of ATM Protein

2001 ◽  
Vol 12 (5) ◽  
pp. 1199-1213 ◽  
Author(s):  
Gregory G. Oakley ◽  
Lisa I. Loberg ◽  
Jiaqin Yao ◽  
Mary A. Risinger ◽  
Remy L. Yunker ◽  
...  
Keyword(s):  
Dna Replication ◽  
Uv Radiation ◽  
Excision Repair ◽  
Genetic Disorder ◽  
Protein A ◽  
Dna Recombination ◽  
Delayed Response ◽  
Replication Intermediates

Exposure to DNA-damaging agents triggers signal transduction pathways that are thought to play a role in maintenance of genomic stability. A key protein in the cellular processes of nucleotide excision repair, DNA recombination, and DNA double-strand break repair is the single-stranded DNA binding protein, RPA. We showed previously that the p34 subunit of RPA becomes hyperphosphorylated as a delayed response (4–8 h) to UV radiation (10–30 J/m2). Here we show that UV-induced RPA-p34 hyperphosphorylation depends on expression of ATM, the product of the gene mutated in the human genetic disorder ataxia telangiectasia (A-T). UV-induced RPA-p34 hyperphosphorylation was not observed in A-T cells, but this response was restored by ATM expression. Furthermore, purified ATM kinase phosphorylates the p34 subunit of RPA complex in vitro at many of the same sites that are phosphorylated in vivo after UV radiation. Induction of this DNA damage response was also dependent on DNA replication; inhibition of DNA replication by aphidicolin prevented induction of RPA-p34 hyperphosphorylation by UV radiation. We postulate that this pathway is triggered by the accumulation of aberrant DNA replication intermediates, resulting from DNA replication fork blockage by UV photoproducts. Further, we suggest that RPA-p34 is hyperphosphorylated as a participant in the recombinational postreplication repair of these replication products. Successful resolution of these replication intermediates reduces the accumulation of chromosomal aberrations that would otherwise occur as a consequence of UV radiation.

scholarly journals Purinergic Modulation of Interleukin-1β Release from Microglial Cells Stimulated with Bacterial Endotoxin

1997 ◽  
Vol 185 (3) ◽  
pp. 579-582 ◽  
Author(s):  
Davide Ferrari ◽  
Paola Chiozzi ◽  
Simonetta Falzoni ◽  
Stefania Hanau ◽  
Francesco Di  Virgilio
Keyword(s):  
Plasma Membrane ◽  
P2x7 Receptor ◽  
Purinergic Receptor ◽  
Present Report ◽  
Physiological Role ◽  
Bacterial Endotoxin ◽  
Microglial Cells

Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1β secretion.

scholarly journals A giant posterior mediastinal malignant peripheral nerve sheath tumor and benign neurofibroma in body surface: a case report

BMC Surgery ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yan Zhang ◽  
Hongfei Cai ◽  
Guangchao Lv ◽  
Yang Li
Keyword(s):  
Peripheral Nerve ◽  
Neurofibromatosis Type ◽  
Posterior Mediastinum ◽  
Pathological Examination ◽  
Nerve Sheath Tumor ◽  
Tumor Type ◽  
Peripheral Nerve Sheath Tumor ◽  
Nerve Tumor ◽  
Nerve Sheath ◽  
Posterior Mediastinal

Abstract Background Neurofibromatosis comprises neurofibromatosis type 1 (NF1) and type 2 (NF2). Major tumor type of NF1 are neurofibroma recognized as benign peripheral nerve tumor, malignant peripheral nerve sheath tumor (MPNST), and glioma. Case presentation We report a woman with a special condition, whose tumors in body surfaces were benign neurofibroma and tumors in posterior mediastinum are MPNST. The chest-enhanced CT suggested a round soft tissue density in posteriormediastium. The diagnosis was established by pathology and immunohistochemistry. A single-stage thoracoscopic mediastinal mass resection was performed. The whole operation went smoothly and the CT scan of lungs did not show relapse of tumor three months later. Conclusions The appearance of neurofibroma should draw particular attention to the possibility of developing MPNST. More careful imaging examinations should be carried out, and pathological examination could diagnose it.

scholarly journals Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Uchechukwu T. Agwuegbo ◽  
Emily Colley ◽  
Anthony P. Albert ◽  
Viktor Y. Butnev ◽  
George R. Bousfield ◽  
...  
Keyword(s):  
Super Resolution ◽  
Hek293 Cells ◽  
Camp Signaling ◽  
Camp Production ◽  
Functional Roles ◽  
Menopausal Women ◽  
Resolution Imaging ◽  
Post Menopausal

Follicle-stimulating hormone (FSH) and its target G protein-coupled receptor (FSHR) are essential for reproduction. Recent studies have established that the hypo-glycosylated pituitary FSH glycoform (FSH21/18), is more bioactive in vitro and in vivo than the fully-glycosylated variant (FSH24). FSH21/18 predominates in women of reproductive prime and FSH24 in peri-post-menopausal women, suggesting distinct functional roles of these FSH glycoforms. The aim of this study was to determine if differential FSH glycosylation modulated FSHR oligomerization and resulting impact on cAMP signaling. Using a modified super-resolution imaging technique (PD-PALM) to assess FSHR complexes in HEK293 cells expressing FSHR, we observed time and concentration-dependent modulation of FSHR oligomerization by FSH glycoforms. High eFSH and FSH21/18 concentrations rapidly dissociated FSHR oligomers into monomers, whereas FSH24 displayed slower kinetics. The FSHR β-arrestin biased agonist, truncated eLHβ (Δ121-149) combined with asparagine56-deglycosylated eLHα (dg-eLHt), increased FSHR homomerization. In contrast, low FSH21/18 and FSH24 concentrations promoted FSHR association into oligomers. Dissociation of FSHR oligomers correlated with time points where higher cAMP production was observed. Taken together, these data suggest that FSH glycosylation may modulate the kinetics and amplitude of cAMP production, in part, by forming distinct FSHR complexes, highlighting potential avenues for novel therapeutic targeting of the FSHR to improve IVF outcomes.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

scholarly journals CD47 prevents the elimination of diseased fibroblasts in scleroderma

2020 ◽  
Author(s):  
Tristan Lerbs ◽  
Lu Cui ◽  
Megan E. King ◽  
Tim Chai ◽  
Claire Muscat ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Autoimmune Disease ◽  
Skin Fibrosis ◽  
Transfer Model ◽  
Self Renewal ◽  
Syngeneic Mouse ◽  
Fibrotic Tissue

AbstractScleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression, but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated JUN and increased promotor accessibilities of both JUN and the CD47. Next, we established our scleroderma model demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1-fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study is the first to demonstrate the efficiency of combining different immunotherapies in treating scleroderma and provide a rationale for combining CD47 and IL6 inhibition in clinical trials.

scholarly journals Slug deficiency enhances self-renewal of hematopoietic stem cells during hematopoietic regeneration

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1709-1717 ◽  
Author(s):  
Yan Sun ◽  
Lijian Shao ◽  
Hao Bai ◽  
Zack Z. Wang ◽  
Wen-Shu Wu
Keyword(s):  
Hematopoietic Cells ◽  
Stress Conditions ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Steady State Condition ◽  
Therapeutic Benefits ◽  
Evolutionarily Conserved ◽  
Novel Strategy

Abstract Both extrinsic and intrinsic mechanisms tightly govern hematopoietic stem cell (HSC) decisions of self-renewal and differentiation. However, transcription factors that can selectively regulate HSC self-renewal division after stress remain to be identified. Slug is an evolutionarily conserved zinc-finger transcription factor that is highly expressed in primitive hematopoietic cells and is critical for the radioprotection of these key cells. We studied the effect of Slug in the regulation of HSCs in Slug-deficient mice under normal and stress conditions using serial functional assays. Here, we show that Slug deficiency does not disturb hematopoiesis or alter HSC homeostasis and differentiation in bone marrow but increases the numbers of primitive hematopoietic cells in the extramedullary spleen site. Deletion of Slug enhances HSC repopulating potential but not its homing and differentiation ability. Furthermore, Slug deficiency increases HSC proliferation and repopulating potential in vivo after myelosuppression and accelerates HSC expansion during in vitro culture. Therefore, we propose that Slug is essential for controlling the transition of HSCs from relative quiescence under steady-state condition to rapid proliferation under stress conditions. Our data suggest that inhibition of Slug in HSCs may present a novel strategy for accelerating hematopoietic recovery, thus providing therapeutic benefits for patients after clinical myelosuppressive treatment.

scholarly journals The Role of Merlin/NF2 Loss in Meningioma Biology

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1633 ◽  
Author(s):  
Sungho Lee ◽  
Patrick J. Karas ◽  
Caroline C. Hadley ◽  
James C. Bayley V ◽  
A. Basit Khan ◽  
...  
Keyword(s):  
Early Recognition ◽  
Neurofibromatosis Type ◽  
Genetic Alterations ◽  
In Vivo Models ◽  
Inhibition Of Proliferation ◽  
Nf2 Gene ◽  
Sequencing Studies

Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin’s many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.

scholarly journals The application of resveratrol to mesenchymal stromal cell-based regenerative medicine

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Chenxia Hu ◽  
Lanjuan Li
Keyword(s):  
Regenerative Medicine ◽  
Tissue Injury ◽  
Lineage Commitment ◽  
Root Extract ◽  
Therapeutic Effects ◽  
Aging Effects ◽  
Chronic Injury ◽  
Self Renewal

Abstract Currently, the transplantation of mesenchymal stromal cells (MSCs) has emerged as an effective strategy to protect against tissue and organ injury. MSC transplantation also serves as a promising therapy for regenerative medicine, while poor engraftment and limited survival rates are major obstacles for its clinical application. Although multiple studies have focused on investigating chemicals to improve MSC stemness and differentiation in vitro and in vivo, there is still a shortage of effective and safe agents for MSC-based regenerative medicine. Resveratrol (RSV), a nonflavonoid polyphenol phytoalexin with a stilbene structure, was first identified in the root extract of white hellebore and is also found in the roots of Polygonum cuspidatum, and it is widely used in traditional Chinese medicine. RSV is a natural agent that possesses great therapeutic potential for protecting against acute or chronic injury in multiple tissues as a result of its antioxidative, anti-inflammatory, and anti-cancer properties. According to its demonstrated properties, RSV may improve the therapeutic effects of MSCs via enhancing their survival, self-renewal, lineage commitment, and anti-aging effects. In this review, we concluded that RSV significantly improved the preventive and therapeutic effects of MSCs against multiple diseases. We also described the underlying mechanisms of the effects of RSV on the survival, self-renewal, and lineage commitment of MSCs in vitro and in vivo. Upon further clarification of the potential mechanisms of the effects of RSV on MSC-based therapy, MSCs may be able to be more widely used in regenerative medicine to promote recovery from tissue injury.

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