Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis

Stępkowski, Tomasz M.; Kruszewski, Marcin

doi:10.1016/j.freeradbiomed.2011.01.033

Cited by 173 publications

(123 citation statements)

References 98 publications

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“…It has been postulated that there is cross‐talk between autophagy and Nrf2/Keap1 signaling (Jain et al., 2010; Stepkowski & Kruszewski, 2011). We tested for this by manipulating autophagy and CncC (Nrf2) alone and in combination.…”

Section: Discussionmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

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Section: Discussionmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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“…Therefore, the present study paid attention to the effect of Nrf2 downregulation on autophagy induced by TMZ. Substantial evidence showed that Nrf2 and apoptosis pathway may cross-talk mediated by the Keap1-binding proteins such as phosphoglycerate mutase 5 (PGAM5), prothymosin α (ProTα), fetal Alz-50 clone 1 (FAC1), and p62 (SQSTM1) (25). Hence, in order to exclude the role of Nrf2 on apoptosis induced by TMZ, we chose a certain dose and time of TMZ based on previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, autophagy has potential utility as a target for GBM therapy (23,24). Recently, several experts proposed the hypothesis that there may be cross-talk between Nrf2/Keap1 and autophagy pathways (25). Thus, the aim of the current study was to determine whether Nrf2 can influence autophagy in U251 human glioma cell line after TMZ.…”

Section: Introductionmentioning

confidence: 92%

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

et al. 2012

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Abstract. Glioblastoma multiforme (GBM) and oxidative stress are closely linked. Oxidative stress affects many signaling pathways and may cause the induction of autophagy. The NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is the main pathway responsible for cell defense against oxidative stress and Nrf2 is a critical transcription factor related with cancer multidrug resistance. However, the relation between Nrf2 and regulation of autophagy is not well understood. In this study, we used temozolomide (TMZ), which inhibited the viability of GBM cells mainly by inducing autophagic cell death and explored the role of Nrf2 downregulation on autophagy induced by TMZ in GBM cells. In U251-Si-Nrf2 48 h after transfection the protein levels of Nrf2 were significantly downregulated, while the protein levels of LC3B-II increased by western blot analysis. Knockdown of Nrf2 also led to a significant increase of autophagic vacuoles and acidic vesicular organelles (AVOs), revealed by trans mission electron microscopy (TEM) and acridine orange (AO) staining using flow cytometry. Collectively, these findings demonstrate that knockdown of Nrf2 can enhance the basal level of autophagy in the U251 glioma cell line. Furthermore, after the treatment with TMZ (100 µM) for 3 days, the U251-Si-Nrf2 transfected cells showed less viability rate by cell counting kit-8 (CCK-8) assay and the levels of autophagy increased obviously through analysis of western blot and AO staining using flow cytometry. Taken together, our results suggest that knockdown of Nrf2 may enhance autophagy induced by TMZ in the U251 glioma cell line, which should be further evaluated for novel anticancer activity.

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“…This disrupts binding to the DLG domain on NFE2L2, thereby inhibiting NFE2L2 degradation. Subsequent phosphorylation or additional interactions facilitate complete dissociation of NFE2L2 which can migrate into the nucleus and activate transcription of several genes involved in reactive oxygen species (ROS) scavenging, detoxification and repair, and mitochondrial function (Stępkowski and Kruszewski 2011).…”

Section: Antioxidant Responsementioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis

Cited by 173 publications

References 98 publications

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

p62/SQSTM1 at the interface of aging, autophagy, and disease

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