ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2015
Tumor suppressor ataxia telangiectasia mutated functions downstream of TGF-β1 in orchestrating profibrotic responses.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 37 citations in OpenAlex.
- Involvement of c-Myc/WWP1/TRIM65 Axis in Renal Fibrosis.Biomolecules · 2026Article
- Ataxia-telangiectasia mutated activation mediates transforming growth factor beta signaling in acetaminophen-induced liver injury in mice.Physiological reports · 2025Article
- RAD18 promotes cell malignant behaviors of esophageal squamous cell carcinoma by modulating ATM/STAT3/PD-L1.Chromosoma · 2025Article
- Identification and validation of biomarkers related to ferroptosis in idiopathic pulmonary fibrosis.Scientific reports · 2025Article
- Crosstalk between ferroptosis and innate immune in diabetic kidney disease: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- Crosstalk between PML and p53 in response to TGF-β1: A new mechanism of cardiac fibroblast activation.International journal of biological sciences · 2023Article
- ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance.Cancer research · 2022Article
- Emerging role of tumor suppressor p53 in acute and chronic kidney diseases.Cellular and molecular life sciences : CMLS · 2022Review
- Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets.Cancers · 2022Review
- Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?Frontiers in immunology · 2022Article
- PAI-1 induction during kidney injury promotes fibrotic epithelial dysfunction via deregulation of klotho, p53, and TGF-β1-receptor signaling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney.Frontiers in cell and developmental biology · 2021Review
- Inhibition of NADPH oxidase alleviates germ cell apoptosis and ER stress during testicular ischemia reperfusion injury.Saudi journal of biological sciences · 2020Article
- Article
- TGF-β1-p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Review
- Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney diseaseFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments.Biomolecules · 2019Review
- Review
- Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- TGF-β1/p53 signaling in renal fibrogenesis.Cellular signalling · 2018Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Effective therapy to prevent organ fibrosis, which is associated with more than half of all mortalities, remains elusive. Involvement of tumor suppressor ataxia telangiectasia mutated (ATM) in the TGF-β1 pathway related to renal fibrosis is largely unknown. ATM activation (pATM(Ser1981)) increased 4-fold in the tubulointerstitial region of the unilateral ureteral obstruction-injured kidney in mice correlating with SMAD3 and p53(Ser15) phosphorylation and elevated levels of p22(phox) subunit of the NADPH oxidases (NOXs), and fibrotic markers, plasminogen activator inhibitor-1 (PAI-1), and fibronectin, when compared to contralateral (contra) or sham controls. In fact, ATM is rapidly phosphorylated at Ser(1981) by TGF-β1 stimulation. Stable silencing and pharmacologic inhibition of ATM ablated TGF-β1-induced p53 activation (>95%) and subsequent PAI-1, fibronectin, connective tissue growth factor, and p21 expression in human kidney 2 (HK-2) tubular epithelial cells and normal rat kidney-49 fibroblasts (NRK-49F). ATM or p53 depletion in HK-2 cells, moreover, bypassed TGF-β1-mediated cytostasis evident in control short hairpin RNA-expressing HK-2 cells. Interestingly, stable silencing of NOX subunits, p22(phox) and p47(phox), in HK-2 cells blocked TGF-β1-induced pATM(Ser1981) (>90%) and target gene induction via p53-dependent mechanisms. Furthermore, NRK-49F fibroblast proliferation triggered by conditioned media from TGF-β1-stimulated, control vector-transfected HK-2 cells decreased (∼ 50%) when exposed to conditioned media from ATM-deficient, TGF-β1-treated HK-2 cells. Thus, TGF-β1 promotes NOX-dependent ATM activation leading to p53-mediated fibrotic gene reprogramming and growth arrest in HK-2 cells. Furthermore, TGF-β1/ATM-initiated paracrine factor secretion by dysfunctional renal epithelium promotes interstitial fibroblast growth, suggesting a role of tubular ATM in mediating epithelial-mesenchymal cross-talk highlighting the translational benefit of targeting the NOX/ATM/p53 axis in renal fibrosis.
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