p53 induces ARTS to promote mitochondrial apoptosis

Hao, Qian; Chen, Jiaxiang; Liao, Jingling; Huang, Yun; Gan, Yu; Larisch, Sarit; Zeng, Shelya X.; Lu, Hua; Zhou, Xiang

doi:10.1038/s41419-021-03463-8

Cited by 32 publications

(23 citation statements)

References 41 publications

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“…Following nutlin-3 treatment, p53 levels increase rapidly, and p53 is either translocated to the nucleus, where it regulates transcription, or localized to mitochondria ( Figure 1 ). It has been hypothesized that the indirect effects of MDM2 inhibitors on the nuclear transcription machinery might contribute to their cytotoxicity by inducing the transcription of pro-apoptotic genes, such as NFRSF10B/TRAIL-R2 ( 47 , 48 ), PUMA ( 48 – 51 ), BAX ( 51 – 54 ) and the apoptosis-related protein in TGF-β signaling pathway ARTS ( 55 ). However, several studies have shown that inhibition of p53 transcriptional activity (by other agents) significantly increases MDM2 inhibitors-mediated cytotoxicity ( 44 , 56 – 58 ).…”

Section: Action Of Mdm2 Inhibitors On Nuclear Gene Transcription and ...mentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.

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Section: Action Of Mdm2 Inhibitors On Nuclear Gene Transcription and ...mentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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“…Inducers of p53 can increase the expression of ARTS, and the blocking of p53 can diminish the expression of ARTS under various stress conditions. These findings indicate that ARTS and p53 act synergistically on apoptosis involving mitochondria [71].…”

Section: Discussionmentioning

confidence: 72%

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Hsu

Hung

Tsai

et al. 2021

IJMS

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Parkinson’s disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin–proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

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“…Another mode of action is the non‐transcription‐dependent mitochondrial mechanism, namely, direct translocation of P53 out of the nucleus, inducing the release of cytochrome C in the mitochondrial membrane space, activating the caspase cascade, and finally executing apoptosis by cleaved‐caspase‐3 to promote the mitochondrial apoptosis pathway. P53‐mediated apoptosis is an important way for P53 to act as a tumor suppressor gene 39‐41 . Therefore, P53, P21, caspase‐3, cleaved‐caspase‐3, which are key proteins regulating the cell cycle and apoptosis process, were selected to verify the role of the rapeseed peptide in inhibiting the proliferation process of HepG2 cells.…”

Section: Resultsmentioning

confidence: 99%

Rapeseed peptide inhibits HepG2 cell proliferation by regulating the mitochondrial and P53 signaling pathways

Wang

et al. 2022

J Sci Food Agric

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Background Rapeseed peptide, extracted from rapeseed protein, is known to have a variety of biological activities. In this study, the anti‐proliferation effect and molecular mechanism of rapeseed peptide on HepG2 cells were investigated. Results In vitro anticancer experiments showed that the rapeseed peptide NDGNQPL could inhibit HepG2 cell proliferation in a concentration‐dependent manner [half maximal inhibitory concentration (IC50), 1.56 mmol L−1). HepG2 cells were induced by NDGNQPL at a 0.5 mmol L−1 concentration and exhibited a 28.39 ± 0.80% apoptosis rate and a cell cycle arrest in the G0/G1 phase. Meanwhile, rapeseed peptide induced a decrease in mitochondrial membrane potential, an increase in reactive oxygen species (ROS) release, and changes in the nuclear morphology of HepG2 cells, indicating that rapeseed peptide could induce cell apoptosis through the mitochondrial pathway. In addition, rapeseed peptide activated the proliferation‐related P53 signaling pathway, in which the expression levels of P53, P21, and cleaved‐caspase3 were up‐regulated, while the expression levels of murine double minute 2 (MDM2) were down‐regulated. In molecular docking simulations, NDGNQPL exhibited a good affinity for the MDM2 molecule, which supported the notion that the rapeseed peptide is able to inhibit MDM2, a negative regulator of P53. Conclusion The current results indicate that the rapeseed‐derived NDGNQPL peptide has the potential to inhibit the proliferation of HepG2 cells and promote human health. © 2022 Society of Chemical Industry.

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p53 induces ARTS to promote mitochondrial apoptosis

Cited by 32 publications

References 41 publications

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Rapeseed peptide inhibits HepG2 cell proliferation by regulating the mitochondrial and P53 signaling pathways

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