Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction

Oh, Stephanie E.; Mouradian, M. Maral

doi:10.1016/j.redox.2017.09.008

Cited by 102 publications

(59 citation statements)

References 91 publications

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“…The ERK1/2 pathway is a classic mitogen-activated protein kinase signaling cascade that regulates cell proliferation and growth (34,35). In the present study, it was observed that silencing of AQP5 inhibited ERK1/2 signaling, consistent with the observations of prior studies (17,36).…”

Section: Discussionsupporting

confidence: 92%

Silencing of aquaporinï¿½5 inhibits the growth of A549 lung cancer cells in vitro and in vivo

Zhou

et al. 2018

Int J Oncol

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The water channel protein aquaporin 5 (AQP5) is highly expressed in numerous tumors. However, its expression pattern and functions in lung cancer in humans remain unknown. In the present study, the role of AQP5 in the development of lung malignancies was examined. A short hairpin RNA construct targeting AQP5 mRNA was transfected into A549 cells to generate a lung cancer cell line in which AQP5 expression was stably silenced. In vitro and in vivo experiments were then performed to establish the effects of AQP5 on A549 cell apoptosis, proliferation and cell cycle progression. The results demonstrated that AQP5 silencing significantly inhibited the proliferation and promoted the apoptosis of A549 lung cancer cells in vitro and in vivo. In addition, it resulted in decreased activation of the extracellular signal-regulated kinase 1/2 signaling pathway in A549 cells, and reduced levels of the downstream proteins c‑Fos and phosphorylated cAMP response element-binding protein. Furthermore, inhibition of AQP5 expression effectively reduced the tumorigenicity of A549 cells in vivo. In conclusion, silencing of AQP5 suppressed the growth of A549 cells in vitro and in vivo, suggesting that it may serve as a therapeutic target in lung cancer.

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Section: Discussionsupporting

confidence: 92%

Silencing of aquaporinï¿½5 inhibits the growth of A549 lung cancer cells in vitro and in vivo

Zhou

et al. 2018

Int J Oncol

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“…We found that 6-OHDA treatment of dopaminergic SH-SY5Y cells caused 3-fold increase in SNCA expression which is consistent with a previous research that shows 5′-UTR of SNCA is upregulated in response to cellular stress factors like MPP+, FeSO4 and 6-OHDA and increases α-synuclein expression in HEK-293T cells [5]. DJ-1 is known to play a role as an oxidative stress sensor, upregulates at first hours of oxidative stimuli and activates Elk1, an ETS domain containing transcription factor as a neuroprotection response [6]. To determine if Elk-1 overexpression is neuroprotective, we have cotransfected WT or A53T overexpressing cells with Elk1 and found that Elk1 expression together A53T mutant decreased cell viability (data not shown).…”

Section: Discussionsupporting

confidence: 91%

Validation of an In-Vitro Parkinson’s Disease Model for the Study of Neuroprotection

Yiğit

Sönmez

Söğüt

et al. 2018

The 2nd International Cell Death Research Congress

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Parkinson’s disease (PD) is the second most common neurodegenerative disease with an estimation of 10 million people living with the disease and it is increasing in prevalence every year. Familial cases of PD are source of valuable information to determine genetical risk factors yet sporadic cases can emerge from distinct mechanisms so, identifying common pathways of familial and sporadic cases of PD may provide worthwhile insights to determine underlying mechanisms through the progression. LRRK2 mutations are the most common indicators of both sporadic and familial cases of PD and α-synuclein aggregation is one of the hallmarks of both cases of PD as well as in other synucleinopathies. As in the case of most neurological diseases, human studies addressing the molecular basis of pathology are generally restricted to post-mortem materials. For this reason, cell culture systems and animal models are widely used. There are two main approaches for modelling PD: genetically constructed PD models and neuroxin-based models. In this study, we aim to construct and compare both approaches by overexpressing wild-type (WT) and A53T mutant α-synuclein and treating cells with well-known neurotoxin 6-hydroxidopamine (6-OHDA) using dopaminergic human neuroblastoma SH-SY5Y cell line. Our findings suggest that WT or A53T α-synuclein overexpression by itself is not sufficient to cause significant toxicity in SH-SY5Y cells in the presented time scale. As expected, 6-OHDA treatment caused toxicity with an IC50 value of ~100 µM. In addition, 6-OHDA treatment causes 3- and 2.5-fold increase in SNCA and LRRK2 expression respectively.

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“…In addition, the results about the suppression of ferroptosis were consist with MGO detoxification ability as DJ-1 ΔC3 and L187E mutants lost the inhibition of ferroptosis compared with DJ-1 WT. Besides, the suppression was more obvious in DJ-1 ΔC3 and L187E mutants than V51C mutant, indicating that the hydrophobic C terminus may have other effects such as involving regulation of signaling pathway [4, 6, 38]. All these data supported our previous discovery that DJ-1 was a negative modulator of ferroptosis providing new opportunities to facilitate ferroptosis-based cancer therapy [14].…”

Section: Discussionsupporting

confidence: 78%

C Terminus of DJ-1 Determines Its Homodimerization, Deglycation Activity and Suppression of Ferroptosis

Jiang

Chen

et al. 2020

Preprint

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23DJ-1 is a multi-functional protein related to cancer and autosomal early-onset Parkinson 24 disease (PD). Besides the well-documented antioxidative stress activity, recent studies suggest 25 that DJ-1 has the deglycation enzymatic activity and the anti-ferroptosis function. Although it 26 has been demonstrated that DJ-1 forms the homodimerization, which dictates its antioxidative 27 stress activity, the relationship between the dimeric structure and newly reported activities 28 remains largely elusive. In this study, we find that the deletion mutation of the last 3 amino 29 acids at C terminus of DJ-1 disrupts its homodimerization in both transfected and purified DJ-30 1 protein. Further study shows that hydrophobic L187 residue is of great importance for DJ-1 31 homodimerization. In addition, the ability in methylglyoxal detoxification is almost abolished 32 in the mutation of deleting last 3 residues at C terminus (ΔC3) and point mutant L187E 33 compared with wild type DJ-1 (DJ-1 WT). We also find that the suppression of ferroptosis is 34 fully inhibited by ΔC3 and L187E while partially suppressed by V51C. Thus, our findings show 35 that C terminus of DJ-1 is crucial for its homodimerization, deglycation activity and 36 suppression of ferroptosis. 37 38 Keywords 39 DJ-1, C-terminus, homodimerization, deglycation activity, anti-ferroptosis 40 41 42 43 44

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Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction

Cited by 102 publications

References 91 publications

Silencing of aquaporinï¿½5 inhibits the growth of A549 lung cancer cells in vitro and in vivo

Silencing of aquaporinï¿½5 inhibits the growth of A549 lung cancer cells in vitro and in vivo

Validation of an In-Vitro Parkinson’s Disease Model for the Study of Neuroprotection

C Terminus of DJ-1 Determines Its Homodimerization, Deglycation Activity and Suppression of Ferroptosis

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