Role of Reactive Oxygen Species in TGF-β1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells

Rhyu, Dong Young; Yang, Yanqiang; Ha, Hunjoo; Lee, Geun Taek; Song, Joo Seok; Uh, Soo Taek; Lee, Hi Bahl

doi:10.1681/asn.2004050425

Cited by 490 publications

(427 citation statements)

References 38 publications

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“…The mechanism by which TGF-β induces DDR is unclear. However, TGF-β is known to induce reactive oxygen species that can promote EMT, oxidative damage to DNA, and genomic instability in mouse mammary epithelial cells (25,26). Our data demonstrate that in HOXB9-expressing cells the induction of γ-H2AX and 53BP1 foci before irradiation and accelerated DDR after ionizing radiation are mediated in part through the HOXB9-TGF-β-ATM axis.…”

Section: Discussionmentioning

confidence: 69%

Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses

Chiba

Comaills

Shiotani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the doublestranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-β, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9-TGF-β-ATM axis on checkpoint activation and DNA repair, suggesting that TGF-β may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9-overexpressing breast tumors.

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Section: Discussionmentioning

confidence: 69%

Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses

Chiba

Comaills

Shiotani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…TGF-b can induce an ROS- PNC1 regulates mitochondrial function and EMT C Favre et al dependent EMT in epithelial cells (Rhyu et al, 2005). As shown in Figure 7c, control MCF-7 cells lost E-cadherin expression when stimulated with TGF-b, whereas cells overexpressing PNC1 retained E-cadherin levels.…”

Section: Ros As Shown Inmentioning

confidence: 84%

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

et al. 2010

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The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1a signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelialmesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-b. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction.

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“…31,32 In contrast, it was recently reported that ROS production inhibits the EMT in prostate cancer cells. 58 Because the EndMT is also observed in tumor cells, it would be interesting to explore whether oxidative stress inhibits the EndMT in cancer cells.…”

Section: Discussionmentioning

confidence: 95%

“…Human epidermal keratinocytes exposed to H 2 O 2 showed protein expression that was consistent with the EMT, 31 and similar results were founded in renal tubular epithelial cells. 32 In the same way, chromium-induced EMT is dependent on intracellular ROS in lung epithelial cells. 33 A specialized EMT process is the endothelial-to-mesenchymal transition (EndMT).…”

mentioning

confidence: 98%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

122

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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Role of Reactive Oxygen Species in TGF-β1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells

Abstract: Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-␤1 is

Cited by 490 publications

References 38 publications

Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses

Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

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