Negative Regulation of the Keap1-Nrf2 Pathway by a p62/Sqstm1 Splicing Variant

Kageyama, Shun; Saito, Tetsuya; Obata, Miki; Koide, Ryohei; Ichimura, Yoshinobu; Komatsu, Masaaki

doi:10.1128/mcb.00642-17

Cited by 71 publications

(53 citation statements)

References 44 publications

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“…(90)]. Nrf2 transactivation is subject to epigenetic regulation that can be suppressed, with a consequence of inhibiting Nrf2 target gene expression (1,91–93). An important unanswered question is whether Nrf2 expression affects normal tissue radiation sensitivity in humans as it does in mice.…”

Section: Resultsmentioning

confidence: 99%

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

et al. 2018

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The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell’s response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2’s role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD5030. An Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after bone marrow transplantation is not yet resolved. Irradiation of the lung induces pulmonary pneumonitis and fibrosis. Loss of Nrf2 promotes TGF-β/Smad signaling that induces ATF3 suppression of Nrf2-mediated target gene expression. This, in turn, results in elevated reactive oxygen species (ROS) and isolevuglandin adduction of protein that impairs collagen degradation, and may contribute to radiation-induced chronic cell injury. Loss of Nrf2 impairs ΔNp63 stem/progenitor cell mobilization after irradiation, while promoting alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts. These studies identify Nrf2 as an important factor in the radiation response of normal tissue.

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Section: Resultsmentioning

confidence: 99%

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

et al. 2018

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“…Noticeably, the Keap1 protein, rather than mRNA, levels are significantly reduced in Nrf1α / cells, albeit its binding partner p62, acting as a major regulator of Keap1 to the autophagic degradation (Kageyama et al, 2018), is strikingly down-regulated in Nrf1α / cells. Thus, we postulate that a p62-independent mechanism may account for the Keap1 protein degradation and also is reinforced in Nrf1α / cells.…”

Section: Discussionmentioning

confidence: 96%

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

Qiu

Wang

et al. 2018

Preprint

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HIGHLIGHTS  Opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2  Malignant growth of Nrf1 / -derived tumor is prevented by silencing Nrf2  Hyper-activation of Nrf2 by Nrf1 / results from decreased Keap1 and PTEN  Nrf1 / -tumor is repressed by Nrf2 /TA , but unaltered by its active caNrf2 ΔN SUMMARY Liver-specific knockout of Nrf1 in mice leads to non-alcoholic steatohepatitis with dyslipidemia, and its deterioration results in spontaneous hepatoma, but the underlying mechanism remains elusive. A similar pathological model is herein reconstructed by using human Nrf1-specific knockout cell lines. We demonstrated that a marked increase of the inflammation marker COX2 in Nrf1 / cells. Loss of Nrf1 leads to hyperactivation of Nrf2, which results from substantial decreases in both Keap1 and PTEN in Nrf1 / cells. Further investigation of xenograft mice showed that malignant growth of Nrf1 / -derived tumor is almost abolished by silencing Nrf2, while Nrf1 / -tumor is markedly repressed by inactive Nrf2 /TA , but unaffected by a priori constitutive activator of caNrf2 ΔN . Mechanistic studies unraveled there exist opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2. Collectively, Nrf1 manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity, while Nrf2 can directly activate the transcriptional expression of Nrf1 to form a negative feedback loop.

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“…Meanwhile, persistent activation of p62–Keap1–Nrf2 pathway has been shown to be involved in liver tumorigenesis in mice ( 6 , 22 ). More recently, we demonstrated that overexpression of a p62 variant lacking KIR mitigates Nrf2 activation ( 68 ). These results suggest that phopsho-p62 could be a novel target for cancer therapy as described in Ref.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 98%

Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer

Ichimura

Komatsu

2018

Front. Oncol.

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Autophagy and the Keap1–Nrf2 system are major cellular defense mechanisms against metabolic and oxidative stress. These two systems are linked via phosphorylation of the ubiquitin binding autophagy receptor protein p62/SQSTM1 in the p62–Keap1–Nrf2 pathway. The p62–Keap1–Nrf2 pathway plays a protective role in normal cells; however, recent studies indicate that this pathway induces tumorigenesis of pre-malignant cells, and promotes the growth and drug resistance of tumor cells via metabolic reprogramming mediated by Nrf2 activation. These findings suggest that impairment of autophagy is involved in the acquisition of malignancy and maintenance of tumors, and furthermore, that p62/SQSTM1 could be a potential target for chemotherapy in cancers that harbor excess p62.

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Negative Regulation of the Keap1-Nrf2 Pathway by a p62/Sqstm1 Splicing Variant

Cited by 71 publications

References 44 publications

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer

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