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Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation

ABSTRACT: Here we report that Axitinib, an inhibitor of VEGFRs currently in use as a second line treatment for advanced renal cell carcinoma, promotes senescence of human endothelial cells in vitro. Mechanistically, this requires oxidative stress-dependent activation of the Ataxia Telangiectasia Mutated (ATM) kinase. Induction of oxidative stress-related genes distinguishes the response of endothelial cells to Axitinib from that to doxorubicin

ORGANISM(S): Homo sapiens

PROVIDER: GSE126426 | GEO | 2019/07/02

REPOSITORIES: GEO

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ROS-activated ATM-dependent phospho-signaling

Project description:ATM (ataxia-telangiectasia mutated) protein plays a central role in phosphorylating a network of proteins in response to DNA double strand breaks. These phosphorylated proteins function in signalling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair and regulating gene expression. We employed a modified TiSH global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and A-T cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,612 phosphorylation sites including 6,650 high confidence sites mapping to 2,536 unique proteins.

2016-01-04 | PXD002850 | Pride

Transcription profiling of ATM +/+, ATM +/- and ATM -/- human lymphoblastoid cell lines exposed to 5 Gy IR at 0, 4 and 24 hours to identify expression phenotypes in Ataxia Telangiectasia carriers and patients

Project description:Transcription profiling of ATM (Ataxia Telangiectasia Mutated) +/+ (Control), ATM +/- (AT Carrier) and ATM -/- (AT patient) human lymphoblastoid cell lines exposed to 5 Gy IR at 0, 4 and 24 hours to identify expression phenotypes in Ataxia Telangiectasia carriers and patients

2008-07-29 | E-TABM-321 | biostudies-arrayexpress

ATM-knockout on total and phosphorylation proteomes of cortical brain organoids

Project description:ATM (ataxia telangiectasia mutated) kinase is crucial to a wide range of human developmental disorders and adult/pediatric malignancies. Its mutations are causally tied to ataxia telangiectasia, a multi-systemic congenital disorder mainly affecting brain and blood systems. We generated 4 separate ATM-knockout human pluripotent stem cell lines and differentiated them to form 3-dimensional brain cortical brain organoids. Brain cortical organoids are an excellent model of human developing cortex. Using these analyses, we identified ATM-dependent phosphorylation predominantly influences factors in neurogenesis, neuronal differentiation, cell morphogenesis, and microtubule cytoskeleton as well as kinases involved in ATM, BNDF, and WNT signaling, G2/M checkpoint, and p53 regulation. These findings have broad implications about diseases associated with ATM, including ataxia telangiectasia.

2024-07-25 | PXD041699 | Pride

12-month-old ATM-null mouse cerebellar transcriptome

Project description:In cerebellar atrophy of 12-month-old ATM-null mice, transcriptome upregulations concern most neurotransmission and neuropeptide pathways, while downregulations affect prominently Itpr1, Usp2 and non-coding RNA In cerebellar atrophy of 12-month-old ATM-null mice, transcriptome upregulations concern most neurotransmission and neuropeptide pathways, while downregulations affect prominently Itpr1, Usp2 and non-coding RNA The autosomal recessive disorder Ataxia-Telangiectasia is caused by dysfunction of stress response protein ATM. In the nucleus of proliferating cells, ATM senses DNA double-strand breaks and coordinates their repair. This role explains T-cell dysfunction and tumor risk. However, it remains unclear whether this function is relevant for postmitotic neurons and underlies the cerebellar atrophy, since ATM is cytoplasmic in postmitotic neurons. Here, we used ATM-null mice that survived early immune deficits by bone-marrow transplantation, and reached initial neurodegeneration stages at 12 months of age. Global cerebellar transcriptomics demonstrated ATM depletion to trigger upregulations in most neurotransmission and neuropeptide systems. Downregulated transcripts were found for the ATM interactome component Usp2, many non-coding RNAs, ataxia genes Itpr1, Grid2, immediate early genes and immunity factors. Allelic splice changes affected prominently neuropeptide machinery, e.g. Oprm1. Validation experiments with stressors were performed in human neuroblastoma cells, where ATM localized only to cytoplasm, similar to brain. Effect confirmation in SH-SY5Y cells occurred better after ATM depletion and osmotic stress better than nutrient / oxidative stress, rather than ATM kinase inhibition or DNA stressor bleomycin. Overall, we provide pioneer observations from a faithful A-T mouse model, which suggest general changes in synaptic and dense-core vesicle stress adaptation.

2023-10-24 | GSE241955 | GEO

ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

Project description:Maintenance of genomic stability depends on the DNA damage response (DDR), a biological barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell cycle checkpoints and DNA repair following DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation (IR) modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression post-transcriptionally. Dysregulation of this DDR RNA operon is likely relevant to lymphoma development in ataxia-telangiectasia individuals. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.

2011-01-05 | GSE25848 | GEO

Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells

Project description:Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function.

2017-09-04 | PXD006648 | Pride

Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation

Project description:Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation

| PRJNA521866 | ENA

ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

2011-01-05 | E-GEOD-25848 | biostudies-arrayexpress

Gene expressioin signatures at basal level in human lymphoblastoid cell lines with different ataxia telangiectasia-mutated (ATM) genotypes

Project description:Transcriptional profiling of human lymphoblastoid cell lines with different ATM genotypes at basal level was compared to extract gene expression signatures that can identify ataxia telangiectasia (AT) carries from non AT carries and AT patients.

2013-04-09 | GSE45848 | GEO

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2006-10-30 | E-MEXP-780 | biostudies-arrayexpress

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