ATM mediated-p53 signaling pathway forms a novel axis for senescence control

Hwang, Sung Mi; Kuk, Myeong Uk; Kim, Jae Won; Lee, Yun Haeng; Lee, Young‐Sam; Choy, Hyon E.; Park, Sang Chul; Park, Taezoon

doi:10.1016/j.mito.2020.09.002

Cited by 13 publications

(4 citation statements)

References 53 publications

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“…The acetylation of P53 at K317 is known to negatively regulate its apoptotic activity, while the increased acetylation level at K36/37 of PARP-2 has been shown to reduce DNA binding and enzyme activitiies ( Chao et al, 2006 ; Haenni et al, 2008 ). Moreover, Atm not only acts on p53 but also plays a role in repairing damaged DNA by increasing the level of acetylation at K3106 ( Wang et al, 2019 ; Hwang et al, 2020 ). Further, the inhibition of Casp3 activity has been shown to reduce PARP cleavage and therefore influence apoptosis ( Sairanen et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Wan

Jiang

et al. 2021

Front. Genet.

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Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Wan

Jiang

et al. 2021

Front. Genet.

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“…The ATM protein, encoded by the ATM serine/threonine kinase (ataxia–telangiectasia mutated; ATM ) gene, regulates glucose homeostasis and is essential for the phosphorylation of AKT. Double-stranded DNA (dsDNA) breaks activate ATM and with it the pro-apoptotic tumour protein p53 (p53), as shown recently (Hwang et al 2020 ). p53 consequently activates Phosphatase and Tensin homolog (PTEN), which inhibits the pathway, downregulating cellular proliferation and metabolism (Bonin et al 2019 ; Chen et al 2005 ; Marty et al 2008 ).…”

Section: Introductionmentioning

confidence: 77%

SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk

Vuorinen

Okolicsanyi

Gyimesi

et al. 2022

J Cancer Res Clin Oncol

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In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair. Heparan sulfate proteoglycans (HSPGs) are ubiquitous molecules found on the cell surface and in the extracellular matrix with essential functions in regulating cell survival, growth, adhesion and as mediators of cell differentiation and migration. HSPGs, particularly the syndecans (SDCs), have been linked to cancers, making them an exciting target for anticancer treatments. In the PI3K/AKT pathway, syndecan-4 (SDC4) has been shown to downregulate AKT Serine/Threonine Kinase (AKT1) gene expression, while the ATM Serine/Threonine Kinase (ATM) gene has been found to inhibit this pathway upstream of AKT. We investigated single-nucleotide polymorphisms (SNPs) in HSPG and related genes SDC4, AKT1 and ATM and their influence on the prevalence of BC. SNPs were genotyped in the Australian Caucasian Genomics Research Centre Breast Cancer (GRC-BC) population and in the Griffith University–Cancer Council Queensland Breast Cancer Biobank (GU-CCQ BB) population. We identified that SDC4-rs1981429 and ATM-rs228590 may influence the development and progression of BC, having the potential to become biomarkers in early BC diagnosis and personalised treatment.

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“…Factors upstream of p53 are also affected and, along with the ATM kinase, play a vital role in the activation of p53 in response to DNA damage [48][49][50][51][52][53][54]. In our dataset, non-sense mutations leading to premature truncated forms of the ATM protein product represented more than one third of all ATM mutated cases, with R250* being the main representative.…”

Section: The P53 Pathwaymentioning

confidence: 93%

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

Karagiannakos

Adamaki

Tsintarakis

et al. 2022

Cancers

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Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.

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ATM mediated-p53 signaling pathway forms a novel axis for senescence control

Cited by 13 publications

References 53 publications

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

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