The NADPH Oxidase Subunit p22 Inhibits the Function of the Tumor Suppressor Protein Tuberin

Block, Karen; Gorin, Yves; New, David; Eid, Assaad A.; Chelmicki, Tomasz; Reed, Amanda Beth; Choudhury, Goutam Ghosh; Parekh, Dipen J.; Abboud, Hanna E.

doi:10.2353/ajpath.2010.090606

Cited by 43 publications

(49 citation statements)

References 37 publications

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“…6,7 Increased levels of kidney reactive oxygen species (ROS), such as angiotensin II-induced and diabetic nephropathies, are found in CKD. [8][9][10][11][12][13] However, low levels of ROS also play important roles in oxygen sensing, neoangiogenesis, and cell survival pathways, which may play protective roles against kidney fibrosis. 14,15 NADPH oxidases (NOXs) are enzymes that produce ROS as primary products.…”

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confidence: 99%

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

Khodo

Dizin

Sossauer³

et al. 2012

Journal of the American Society of Nephrology

126

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NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1a and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD cl1 ) cell line increased TGF-b1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1a and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.

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confidence: 99%

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

Khodo

Dizin

Sossauer³

et al. 2012

Journal of the American Society of Nephrology

126

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“…As only partial (50 %) inhibition was observed after OHT long-term treatment, complete inhibition of p22 phox mRNA transcription appears to be specifically induced by the subsequent fulvestrant treatment. Beside the well-known implication of p22 phox in NADPH oxidase activity, its involvement in renal or pancreatic cancers has also been described in the literature [30]. In the case of renal cancer, a p22 phox -dependent inactivation of the tumor suppressor gene tuberin was evidenced, indicating that this protein might be associated with a cancerous phenotype [30].…”

Section: Discussionmentioning

confidence: 94%

Effect of tamoxifen and fulvestrant long-term treatments on ROS production and (pro/anti)-oxidant enzymes mRNA levels in a MCF-7-derived breast cancer cell line

et al. 2015

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“…The genetic variation and the effects of tumour environmental cues such as oxygen variability might contribute to the tumour heterogeneity and development. The producing and neutralizing of ROS are pivotal in tumour development because many factors, lipids and nucleic acids are downstream targets of ROS 15, 16, 17. Several studies revealed that unregulated and augmented ROS could initiate redox‐linked signalling responses and irreversible injuries in RCC 18, 19.…”

Section: Discussionmentioning

confidence: 99%

A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR‐556 binding

Wang

Yang

Chen

et al. 2018

J Cellular Molecular Medi

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Dysregulation of glutathione‐S‐transferase M3 (GSTM3) has been related to clear cell renal cell carcinoma (ccRCC) in our former study. GSTM3 plays a pivotal role of detoxification and clearance of reactive oxygen species (ROS) in tumour tissues. This study aimed to examine: (1) the associations between GSTM3 single nucleotide polymorphisms (SNPs) and risk of ccRCC, and (2) the potential molecular mechanism accounting for its effects. 5 SNPs in 3′UTR of GSTM3 were initially genotyped in 329 cases and 420 healthy controls. A SNP‐rs1055259 was found to be significantly associated with the susceptibility of ccRCC (OR = 0.59, 95% CI = 0.41‐0.92; P = .019). The minor allele of rs1055259 (G allele) was associated with RCC risk. This SNP was predicted to affect microRNA (miR)‐556 binding to 3′UTR of GSTM3 mRNA. To determine the functional impact, plasmid constructs carrying different alleles of rs1055259 were created. Compared to rs1055259 A‐allele constructs, cells transfected with rs1055259 G‐allele construct had higher transcriptional activity and were less responsive to miR‐556 changes and gene expression. Elevated GSTM3 expression in G‐allele cells was associated with ROS activity and ccRCC development. Taken together, this study indicated that a functional polymorphism of GSTM3 ‐rs1055259 reduced susceptibility of RCC in the Chinese population. It influenced GSTM3 protein synthesis by interfering miR‐556 binding, subsequently suppressed ROS activity and ccRCC progression.

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The NADPH Oxidase Subunit p22 Inhibits the Function of the Tumor Suppressor Protein Tuberin

Cited by 43 publications

References 37 publications

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

Effect of tamoxifen and fulvestrant long-term treatments on ROS production and (pro/anti)-oxidant enzymes mRNA levels in a MCF-7-derived breast cancer cell line

A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR‐556 binding

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