The role of TP53 gain-of-function mutation in multifocal glioblastoma

ABSTRACT Because Staphylococcus aureus strains contain multiple virulence factors, studying their pathogenic role by single-gene inactivation generated equivocal results. To circumvent this problem, we have expressed specific S. aureus genes in the less virulent organism Streptococcus gordonii and tested the recombinants for a gain of function both in vitro and in vivo. Clumping factor A (ClfA) and coagulase were investigated. Both gene products were expressed functionally and with similar kinetics during growth by streptococci and staphylococci. ClfA-positive S. gordoniiwas more adherent to platelet-fibrin clots mimicking cardiac vegetations in vitro and more infective in rats with experimental endocarditis (P < 0.05). Moreover, deletingclfA from clfA-positive streptococcal transformants restored both the low in vitro adherence and the low in vivo infectivity of the parent. Coagulase-positive transformants, on the other hand, were neither more adherent nor more infective than the parent. Furthermore, coagulase did not increase the pathogenicity ofclfA-positive streptococci when both clfA andcoa genes were simultaneously expressed in an artificial minioperon in streptococci. These results definitively attribute a role for ClfA, but not coagulase, in S. aureus endovascular infections. This gain-of-function strategy might help solve the role of individual factors in the complex the S. aureus-host relationship.

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P–422 Acylglycerol Kinase is a new novel marker in preeclampsia

Human Reproduction ◽

10.1093/humrep/deab130.421 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

F Sun ◽

Y Ma ◽

Q Jie ◽

Q Li

Keyword(s):

Cell Proliferation ◽

Potential Function ◽

Formation Rate ◽

Future Application ◽

Migration And Invasion ◽

Trophoblast Cells ◽

Gain Of Function ◽

Acylglycerol Kinase ◽

Function Models

Abstract Study question What is the potential function of Acylglycerol Kinase (AGK) in the pathogenesis of preeclampsia(PE). Summary answer AGK plays an important role in the pathogenesis of PE by influencing the function of the trophoblast cells. What is known already PE is the leading cause of maternal and perinatal mortality and morbidity. The underlying mechanism is still not completely elucidated. Disorder migration, invasion and mitochondria function of trophoblast cells are one of mechanism in preeclampsia. AGK is a subunit of the mitochondrial channel protein complex TIM22, and maintain the stability of mitochondrial structure and function. Studies have shown that AGK is related to the development of various cancers by infecting the cells migration and invasion. It will be interesting to explore the potential function of AGK in the process of early trophoblast development and the pathogenesis of PE. Study design, size, duration Firstly, explore the expression of AGK in PE. Secondly, lentivirus systems was used to generate loss and gain of function models in trophoblast cell line-HTR8/Sneov to study the role of AGK in the pathogenesis of PE. Participants/materials, setting, methods We examined the expression of AGK both in placental tissues from PE patients and normal pregnant patients. Meanwhile, we generated AGK loss and gain of function models in HTR8/Sneov cells by using lentivirus systems. Transwell assays, scratch-wound assays, EDU and plate clone formation assays, cell apoptosis assays, cell cycle assays, ATP concentration, mtDNA level and transmission electron microscopy were used to examine the function of AGK in HTR8/Sneov cells model. Main results and the role of chance In this study, AGK was significantly decreased in the extra-villous trophoblast (EVT) cells in placental tissues of PE patients compared with that in control group by immunohistochemistry. And further confirmed the expression of AGK in placental tissues by QPCR, western blot. We demonstrated that knockdown of AGK in HTR8 dramatically decreased the cell proliferation, migration and invasion. It also showed the significantly lower plate clone formation rate in AGK knockdown -HTR8 cells compare with the WT HTR8 cells. While overexpression of AGK in HTR8 dramatically increased the cell proliferation, migration, invasion and higher plate clone formation rate. Further, we demonstrated that AGK regulated the ATP level and mtDNA level in HTR8 cells model. And we found that knockdown AGK decreased the number of mitochondria, and shown the mitochondrial crista disorder, mitochondrial swelling and dissolution and mitochondrial membrane fragmentation. While overexpression AGK increased the number of mitochondria. Limitations, reasons for caution Although we show that AGK played an important role in the function of HTR8, the study of working mechanism of AGK in PE is still very limited. More studies will be performed to explore its underline mechanism. Wider implications of the findings: This study was the first time to explore the role of AGK in PE. It will help us to better understand the pathogenesis of PE, which might be helpful in future application of novel therapeutic targets in PE. Trial registration number Not applicable

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Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants

Nucleic Acids Research ◽

10.1093/nar/gkn503 ◽

2008 ◽

Vol 36 (16) ◽

pp. 5362-5375 ◽

Cited By ~ 34

Author(s):

A. Restle ◽

M. Farber ◽

C. Baumann ◽

M. Bohringer ◽

K. H. Scheidtmann ◽

...

Keyword(s):

Homologous Recombination ◽

Gain Of Function

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Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Chemotherapy ◽

10.1159/000446361 ◽

2016 ◽

Vol 62 (1) ◽

pp. 43-53 ◽

Cited By ~ 35

Author(s):

Chao He ◽

Lun Li ◽

Xuan Guan ◽

Li Xiong ◽

Xiongying Miao

Keyword(s):

B Cell Lymphoma ◽

Chemotherapeutic Agents ◽

Lymphocytic Leukemia ◽

Chemotherapy Response ◽

Mutant P53 ◽

Gain Of Function ◽

Pubmed Database ◽

Response To Chemotherapy ◽

The Impact

Purpose: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. Methods: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. Results: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. Conclusion: mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.

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PmrB Mutations Promote Polymyxin Resistance of Pseudomonas aeruginosa Isolated from Colistin-Treated Cystic Fibrosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05829-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 1019-1030 ◽

Cited By ~ 106

Author(s):

Samuel M. Moskowitz ◽

Mark K. Brannon ◽

Nandini Dasgupta ◽

Miyuki Pier ◽

Nicole Sgambati ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Lipid A ◽

Clinical Isolates ◽

Gain Of Function ◽

Content Type ◽

Regulatory Systems ◽

Repeated Passage ◽

High Level

ABSTRACTPseudomonas aeruginosacan develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance,P. aeruginosaisolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-functionpmrBalleles that conferred polymyxin resistance to strains with a wild-type orpmrABdeletion background. Double mutantpmrBalleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutantpmrBalleles induced transcription from the promoter of thearnBoperon and stimulated addition of 4-amino-l-arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate thatpmrBgain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains ofP. aeruginosa.

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A Gain-of-Function Mutation in Synaptotagmin-1 Reveals a Critical Role of Ca2+-Dependent Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Binding in Synaptic Exocytosis

Journal of Neuroscience ◽

10.1523/jneurosci.3804-06.2006 ◽

2006 ◽

Vol 26 (48) ◽

pp. 12556-12565 ◽

Cited By ~ 81

Author(s):

Z. P. Pang ◽

O.-H. Shin ◽

A. C. Meyer ◽

C. Rosenmund ◽

T. C. Sudhof

Keyword(s):

Critical Role ◽

Receptor Complex ◽

Gain Of Function ◽

Attachment Protein ◽

Protein Receptor ◽

Sensitive Factor ◽

Synaptotagmin 1 ◽

Synaptic Exocytosis ◽

Factor Attachment Protein Receptor

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STX2 Promotes Trophoblast Growth, Migration, and Invasion Through Activation of the PI3K-AKT Pathway in Preeclampsia

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.615973 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yan Li ◽

Xian-li Sun ◽

Chun-ling Ma ◽

Chao Li ◽

Ying Zhan ◽

...

Keyword(s):

Molecular Mechanisms ◽

Migration And Invasion ◽

Akt Signaling Pathway ◽

Gain Of Function ◽

Human Trophoblast ◽

Pi3k Inhibitor Ly294002 ◽

Akt Activation ◽

A Subunit ◽

Human Trophoblast Cells

ObjectivesAbnormal trophoblast behaviors during pregnancy contribute to the development of preeclampsia (PE). Syntaxin2 (STX2) has been shown to be a crucial epithelial mediator in numerous diseases. However, the functions of STX2 and the mechanisms underlying its role in PE remain largely unknown. The aim of this study was to explore the role of STX2 on trophoblast biology and unravel the molecular mechanisms that contribute to the development and progression of PE.Materials and MethodsWe first compared the expression of STX2 in placental tissues from women with PE and women with normal pregnancies. Then, we investigated the role of STX2 on trophoblast proliferation, migration and invasion in HTR-8/SVneo and primary human trophoblast cells by loss or gain of function experiments. In addition, co-immunoprecipitation, pulldown and immunofluorescence assays were performed to investigate the co-localization of STX2 with other proteins, and to help clarify the mechanisms underlying STX2-mediated functions on trophoblasts.ResultsWe demonstrated that STX2 expression was downregulated in placental tissues of women with PE compared with those from normal pregnancies. Loss and gain of function experiments further confirmed a role for STX2 in cell proliferation, migration and invasion in trophoblasts. By co-immunoprecipitation, pulldown and immunofluorescence co-localization assays, we revealed that STX2 selectively interacted with p85, a subunit of PI3K, and directly recruited p85 to the cytomembrane, thereby activating the AKT signaling pathway. We further demonstrated that the AKT activation was abolished by the use of a PI3K inhibitor (LY294002), which negatively affected STX2-mediated functions on trophoblasts.ConclusionAll together, our findings point to a crucial role for STX2 in PE progression. Our new insights also suggest that STX2 may be a potential diagnostic tool and a novel therapeutic target for treating PE.

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GABAergic neurons and NaV1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

10.1101/2020.03.14.991158 ◽

2020 ◽

Author(s):

Oana Chever ◽

Sarah Zerimech ◽

Paolo Scalmani ◽

Louisiane Lemaire ◽

Alexandre Loucif ◽

...

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Gabaergic Neurons ◽

Glutamatergic Transmission ◽

Specific Mechanism ◽

Gain Of Function ◽

Glutamatergic Synaptic Transmission ◽

Type 3

AbstractCortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons’ excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K+ build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmission is not required for optogenetic CSD initiation, but glutamatergic transmission is implicated in CSD propagation. Thus, our results reveal the key role of hyper-activation of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine.

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