iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Ge, Wenjie; Zhao, Kunming; Wang, Xingwen; Li, Huayi; Wang, Yuanlin; He, Mengmeng; Xue, Xuting; Zhu, Yifu; Zhang, Cheng; Cheng, Yiwei; Jiang, Shijian; Hu, Ying

doi:10.1016/j.ccell.2017.09.008

Cited by 141 publications

(137 citation statements)

References 62 publications

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“…The major site of ubiquitination appears to be with the Cullin3/Keap1/Rbx1 complex. Oxidative and electrophilic stresses can block Keap1 function while p21 (23), p62, PALB2, IKKB, DPP3 (24) and iASPP (25) can competitively bind to Keap1 and inhibit Nrf2 ubiquitination allowing newly synthesized Nrf2 to translocated to the nucleus (green arrow). Once in the nucleus Nrf2 heterodimerizes with partners such as small Maf transcription factors, binds at AREs present in the proximal promoter of target genes and either induces or suppresses gene expression.…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…(12,19, 20)]. In addition to stress-related activation, a number of proteins [e.g., p21 (21), p62, PALB2, IKKB, DPP3 (22) and iASPP (23)] can competitively bind to Keap1 and inhibit Nrf2 ubiquitination. Inactivation of Keap1 allows de novo synthesized Nrf2 to translocate to the nucleus and either transduce or suppress target genes [Supplementary Fig.…”

Section: Introductionmentioning

confidence: 99%

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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: Supplementary Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Nrf2 activated by external challenges triggers the antioxidant response by transcriptionally activating a wide array of genes to combat the harmful effects of oxidative stress and restore intracellular homeostasis (10)(11)(12). Several factors are involved in the regulation of Nrf2 (13)(14)(15). Recently, lncRNA-maternally expressed 3 was claimed as an Nrf2-regulating lncRNA in tendon fibroblasts (16).…”

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confidence: 99%

Nrf2‐lncRNA controls cell fate by modulating p53‐dependent Nrf2 activation as an miRNA sponge for Plk2 and p21 ^cip1

et al. 2019

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Long noncoding RNA (lncRNA) capable of controlling antioxidative capacity remains to be investigated. Nuclear factor erythroid‐2–related factor 2 (Nrf2) is a central molecule for cellular defense that increases antioxidative capacity. We identified a novel lncRNA named Nrf2‐activating lncRNA (Nrf2‐lncRNA) transcribed from an upstream region of the microRNA 122 gene (MIR122). Nrf2‐lncRNA existed in the cytoplasm, suggestive of its function as a competing endogenous RNA [ceRNA, microRNA (miRNA) sponge]. Nrf2‐lncRNA served as a ceRNA for polo‐like kinase (Plk) 2 and cyclin‐dependent kinase inhibitor 1 (p21cip1) through binding of miRNA 128 and miRNA 224, inducing Plk2/Nrf2/p21cip1 complexation for Nrf2 activation in the cells under p53‐activating conditions (i.e., DNA damage and serum deprivation). Nrf2‐lncRNA expression was suppressed with the initiation of apoptosis, being a rheostat for cell fate determination. Nrf2‐lncRNA levels correlated with the recurrence‐free postsurgery survival rate of patients with hepatocellular carcinoma. Collectively, Nrf2‐lncRNA promotes Plk2 and p21cip1 translation by competing for specific miRNAs and activating Nrf2 under surviving conditions from oxidative stress, implying that Nrf2‐lncRNA serves as a fine‐tuning rheostat for cell fate decision.—Joo, M. S., Shin, S.‐B., Kim, E. J., Koo, J. H., Yim, H., Kim, S. G. Nrf2‐lncRNA controls cell fate by modulating p53‐dependent Nrf2 activation as an miRNA sponge for Plk2 and p21cip1. FASEB J. 33, 7953–7969 (2019). http://www.fasebj.org

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“…The overexpression of iASPP has been reported to promote cancer cell proliferation, invasion, and migration, as well as multidrug resistance of cancers . Herein, we first assessed the effect of iASPP on Burkitt lymphoma cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

miR‐129 targets CDK1 and iASPP to modulate Burkitt lymphoma cell proliferation in a TAp63‐dependent manner

Zou

Chen

et al. 2018

J of Cellular Biochemistry

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Burkitt lymphoma is one of the most common lymphatic system cancers with poor outcome in adult patients. p53-induced apoptosis is a critical signaling for preventing tumor development. Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. However, p53 is frequently mutated in Burkitt lymphoma, which gains novel oncogenic properties. Recently, the p53 family member, p63, became an attractive gene for the therapeutic strategies for patients with cancer. Therefore, we investigated the role of iASPP in the transactivation domain p63 (TAp63)-dependent cell proliferation inhibition in Burkitt lymphoma. We verified that the oncogenic effect of iASPP on Burkitt lymphoma is TAp63 dependent rather than p53 and confirmed that the interaction between CDK1 and iASPP enhanced the inhibitory effect of iASPP on p53 and TAp63. An online tool predicated that miR-129 might bind to 3'-untranslated region of iASPP and CDK1. We revealed that miR-129 acted as a tumor suppressor by inhibiting cancer cell proliferation and inhibiting CDK1 and iASPP via direct binding. An miR-129 inhibitor increased nucleus iASPP and decreased nucleus p53 and TAp63 levels, which could be reversed by the CDK1 knockdown, indicating that miR-129 might target CDK1 to inhibit iASPP phosphorylation, thus hindering iASPP nucleus localization and its inhibitory effect on p53 and TAp63 protein levels. Taken together, miR-129 could targetedly inhibit the expression of CDK1 and iASPP. CDK1 knockdown inhibits iASPP S84/S113 phosphorylation, thus blocking iASPP nucleus localization, suppressing the inhibitory effect of iASPP on p53 and TAp63, and restoring TAp63-induced proliferation inhibition in Burkitt lymphoma cells.

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iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Cited by 141 publications

References 62 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

Nrf2‐lncRNA controls cell fate by modulating p53‐dependent Nrf2 activation as an miRNA sponge for Plk2 and p21 ^cip1

miR‐129 targets CDK1 and iASPP to modulate Burkitt lymphoma cell proliferation in a TAp63‐dependent manner

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iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Cited by 141 publications

References 62 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

Nrf2‐lncRNA controls cell fate by modulating p53‐dependent Nrf2 activation as an miRNA sponge for Plk2 and p21 cip1

miR‐129 targets CDK1 and iASPP to modulate Burkitt lymphoma cell proliferation in a TAp63‐dependent manner

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Nrf2‐lncRNA controls cell fate by modulating p53‐dependent Nrf2 activation as an miRNA sponge for Plk2 and p21 ^cip1