scholarly journals MicroRNA-361-5p slows down gliomas development through regulating UBR5 to elevate ATMIN protein expression

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Jiaoying Jia ◽  
Zhu Ouyang ◽  
Ming Wang ◽  
Wenjia Ma ◽  
Min Liu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ataxia Telangiectasia ◽  
Regulatory Mechanism ◽  
Ataxia Telangiectasia Mutated ◽  
Malignant Phenotype ◽  
Ubiquitin Protein Ligase ◽  
The Relationship ◽  
Insight Into

AbstractMicroRNA (miR)-361-5p has been studied to suppress gliomas development. Based on that, an insight into the regulatory mechanism of miR-361-5p in gliomas was supplemented from ubiquitin protein ligase E3 component N-recognin 5 (UBR5)-mediated ubiquitination of ataxia-telangiectasia mutated interactor (ATMIN). miR-361-5p, ATMIN, and UBR5 levels were clinically analyzed in gliomas tissues, which were further validated in gliomas cell lines. Loss/gain-of-function method was applied to determine the roles of miR-361-5p and UBR5 in gliomas, as to cell viability, migration, invasion, colony formation ability, and apoptosis in vitro and tumorigenesis in vivo. The relationship between miR-361-5p and UBR5 was verified and the interaction between UBR5 and ATMIN was explored. It was detected that reduced miR-361-5p and ATMIN and enhanced UBR5 levels showed in gliomas. Elevating miR-361-5p was repressive in gliomas progression. UBR5 was directly targeted by miR-361-5p. UBR5 can ubiquitinate ATMIN. miR-361-5p suppressed gliomas by regulating UBR5-mediated ubiquitination of ATMIN. Downregulating UBR5 impeded gliomas tumor growth in vivo. Upregulating miR-361-5p targets UBR5 to promote ATMIN protein expression, thus to recline the malignant phenotype of gliomas cells.

scholarly journals Tethering DNA Damage Checkpoint Mediator Proteins Topoisomerase IIβ-binding Protein 1 (TopBP1) and Claspin to DNA Activates Ataxia-Telangiectasia Mutated and RAD3-related (ATR) Phosphorylation of Checkpoint Kinase 1 (Chk1)

2011 ◽  
Vol 286 (22) ◽  
pp. 19229-19236 ◽  
Author(s):  
Laura A. Lindsey-Boltz ◽  
Aziz Sancar
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Mammalian Cells ◽  
Binding Protein ◽  
Effector Proteins ◽  
Ataxia Telangiectasia Mutated ◽  
Checkpoint Kinase ◽  
Atr Kinase

The ataxia-telangiectasia mutated and RAD3-related (ATR) kinase initiates DNA damage signaling pathways in human cells after DNA damage such as that induced upon exposure to ultraviolet light by phosphorylating many effector proteins including the checkpoint kinase Chk1. The conventional view of ATR activation involves a universal signal consisting of genomic regions of replication protein A-covered single-stranded DNA. However, there are some indications that the ATR-mediated checkpoint can be activated by other mechanisms. Here, using the well defined Escherichia coli lac repressor/operator system, we have found that directly tethering the ATR activator topoisomerase IIβ-binding protein 1 (TopBP1) to DNA is sufficient to induce ATR phosphorylation of Chk1 in an in vitro system as well as in vivo in mammalian cells. In addition, we find synergistic activation of ATR phosphorylation of Chk1 when the mediator protein Claspin is also tethered to the DNA with TopBP1. Together, these findings indicate that crowding of checkpoint mediator proteins on DNA is sufficient to activate the ATR kinase.

scholarly journals Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro

2000 ◽  
Vol 97 (19) ◽  
pp. 10389-10394 ◽  
Author(s):  
S. Matsuoka ◽  
G. Rotman ◽  
A. Ogawa ◽  
Y. Shiloh ◽  
K. Tamai ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated

scholarly journals EBV encoded miRNA BART8-3p promotes radioresistance in nasopharyngeal carcinoma by regulating ATM/ATR signaling pathway

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Xiaohan Zhou ◽  
Jialing Zheng ◽  
Ying Tang ◽  
Yanling lin ◽  
Lingzhi Wang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Ataxia Telangiectasia ◽  
Molecular Mechanisms ◽  
Radiation Treatment ◽  
Ataxia Telangiectasia Mutated ◽  
Barr Virus ◽  
Radiotherapy Resistance

Abstract Resistance to radiotherapy is one of the main causes of treatment failure in patients with nasopharyngeal carcinoma (NPC). Epstein-Barr virus (EBV) infection is an important factor in the pathogenesis of NPC, and EBV-encoded microRNAs (miRNAs) promote NPC progression. However, the role of EBV-encoded miRNAs in the radiosensitivity of NPC remains unclear. Here, we investigated the effects of EBV-miR-BART8-3p on radiotherapy resistance in NPC cells in vitro and in vivo, and explored the underlying molecular mechanisms. Inhibitors of ataxia telangiectasia mutated (ATM)/ataxia telangiectasia mutated and Rad3-related (ATR) (KU60019 and AZD6738, respectively) were used to examine radiotherapy resistance. We proved that EBV-miR-BART8-3p promoted NPC cell proliferation in response to irradiation in vitro and associated with the induction of cell cycle arrest at the G2/M phase, which was a positive factor for the DNA repair after radiation treatment. Besides, EBV-miR-BART8-3p could increase the size of xenograft tumors significantly in nude mice. Treatment with KU60019 or AZD6738 increased the radiosensitivity of NPC by suppressing the expression of p-ATM and p-ATR. The present results indicate that EBV-miR-BART8-3p promotes radioresistance in NPC by modulating the activity of ATM/ATR signaling pathway.

scholarly journals Human NDR Kinases Are Rapidly Activated by MOB Proteins through Recruitment to the Plasma Membrane and Phosphorylation

2005 ◽  
Vol 25 (18) ◽  
pp. 8259-8272 ◽  
Author(s):  
Alexander Hergovich ◽  
Samuel J. Bichsel ◽  
Brian A. Hemmings
Keyword(s):  
Plasma Membrane ◽  
Regulatory Mechanism ◽  
Membrane Targeting ◽  
Membrane Translocation ◽  
Cancer Types ◽  
Membrane Bound ◽  
Insight Into ◽  
Constitutively Active

ABSTRACT Human nuclear Dbf2-related kinases (NDRs) are up-regulated in certain cancer types, yet their precise function(s) and regulatory mechanism(s) still remain to be defined. Here, we show that active (phosphorylated on Thr444) and inactive human NDRs are both mainly cytoplasmic. Moreover, NDR kinases colocalize at the plasma membrane with human MOBs (hMOBs), which are recently described coactivators of human NDR in vitro. Strikingly, membrane targeting of NDR results in a constitutively active kinase due to phosphorylation on Ser281 and Thr444 that is further activated upon coexpression of hMOBs. Membrane-targeted hMOBs also robustly promoted activation of NDR. We further demonstrate that the in vivo activation of human NDR by membrane-bound hMOBs is dependent on their interaction and occurs solely at the membrane. By using a chimeric molecule of hMOB, which allows inducible membrane translocation, we found that NDR phosphorylation and activation at the membrane occur a few minutes after association of hMOB with membranous structures. We provide insight into a potential in vivo mechanism of NDR activation through rapid recruitment to the plasma membrane mediated by hMOBs.

scholarly journals Silencing of ataxia-telangiectasia mutated by siRNA enhances the in vitro and in vivo radiosensitivity of glioma

2016 ◽  
Vol 35 (6) ◽  
pp. 3303-3312 ◽  
Author(s):  
YAN LI ◽  
LUCHUN LI ◽  
BO LI ◽  
ZHIJUAN WU ◽  
YONGZHONG WU ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated

scholarly journals Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366

2002 ◽  
Vol 368 (2) ◽  
pp. 507-516 ◽  
Author(s):  
Gopal P. SAPKOTA ◽  
Maria DEAK ◽  
Agnieszka KIELOCH ◽  
Nick MORRICE ◽  
Aaron A. GOODARZI ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Ionizing Radiation ◽  
Ataxia Telangiectasia ◽  
Cellular Responses ◽  
Ataxia Telangiectasia Mutated ◽  
Cancer Syndrome ◽  
Phosphoinositide 3 Kinase

The serine/threonine protein kinase LKB1 functions as a tumour suppressor, and mutations in this enzyme lead to the inherited Peutz—Jeghers cancer syndrome. We previously found that LKB1 was phosphorylated at Thr-366 in vivo, a residue conserved in mammalian, Xenopus and Drosophila LKB1, located on a C-terminal non-catalytic moiety of the enzyme. Mutation of Thr-366 to Ala or Asp partially inhibited the ability of LKB1 to suppress growth of G361 melanoma cells, but did not affect LKB1 activity in vitro or LKB1 localization in vivo. As a first step in exploring the role of this phosphorylation further, we have generated a phosphospecific antibody specifically recognizing LKB1 phosphorylated at Thr-366 and demonstrate that exposure of cells to ionizing radiation (IR) induced a marked phosphorylation of LKB1 at Thr-366 in the nucleus. Thr-366 lies in an optimal phosphorylation motif for the phosphoinositide 3-kinase-like kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated kinase (ATM) and ataxia telangiectasia-related kinase (ATR), which function as sensors for DNA damage in cells and mediate cellular responses to DNA damage. We demonstrate that both DNA-PK and ATM efficiently phosphorylate LKB1 at Thr-366 in vitro and provide evidence that ATM mediates this phosphorylation in vivo. This is based on the finding that LKB1 is not phosphorylated in a cell line lacking ATM in response to IR, and that agents which induce cellular responses via ATR in preference to ATM poorly induce phosphorylation of LKB1 at Thr-366. These observations provide the first link between ATM and LKB1 and suggest that ATM could regulate LKB1.

scholarly journals A novel ataxia-telangiectasia mutated autoregulatory feedback mechanism in murine embryonic stem cells

2009 ◽  
Vol 6 (41) ◽  
pp. 1167-1177 ◽  
Author(s):  
Robert G. Clyde ◽  
Ashley L. Craig ◽  
Lucas de Breed ◽  
James L. Bown ◽  
Leslie Forrester ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Es Cells ◽  
Somatic Cells ◽  
Embryonic Stem ◽  
Adult Stem Cell ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response ◽  
Modelling Approach

Ataxia-telangiectasia mutated (ATM) is known to play a central role in effecting the DNA damage response that protects somatic cells from potentially harmful mutations, and in this role it is a key anti-cancer agent. However, it also promotes repair of therapeutic damage (e.g. radiotherapy) and so frustrates the efficacy of some treatments. A better understanding of the mechanisms of ATM regulation is therefore important both in prevention and treatment of disease. While progress has been made in elucidating the key signal transduction pathways that mediate damage response in somatic cells, relatively little is known about whether these function similarly in pluripotent embryonic stem (ES) cells where ATM is also implicated in our understanding of adult stem cell ageing and in improvements in regenerative medicine. There is some evidence that different mechanisms may operate in ES cells and that our understanding of the mechanisms of ATM regulation is therefore incomplete. We investigated the behaviour of the damage response signalling pathway in mouse ES cells. We subjected the cells to the DNA-damaging agent doxorubicin, a drug that induces double-strand breaks, and measured ATM expression levels. We found that basal ATM gene expression was unaffected by doxorubicin treatment. However, following ATM kinase inhibition using a specific ATM inhibitor, we observed a significant increase in ATM and ataxia-telangiectasia and Rad3 related transcription. We demonstrate the use of a dynamical modelling approach to show that these results cannot be explained in terms of known mechanisms. Furthermore, we show that the modelling approach can be used to identify a novel feedback process that may underlie the anomalies in the data. The predictions of the model are consistent both with our in vitro experiments and with in vivo studies of ATM expression in somatic cells in mice, and we hypothesize that this feedback operates in both somatic and ES cells in vivo . The results point to a possible new target for ATM inhibition that overcomes the restorative potential of the proposed feedback.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

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