TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms

Suzuki, Midori; Asai, Yukino; Kagi, Tomohiro; Noguchi, Takuya; Yamada, Mihoko; Hirata, Yusuke; Matsuzawa, Atsushi

doi:10.3390/ijms21249497

Cited by 18 publications

(12 citation statements)

References 41 publications

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“…To explore the potential roles of LKB1 in DDR induced by cisplatin, we established two independent clones of LKB1 knockout cells (LKB1 KO) in human fibrosarcoma cell line HT1080 by using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9) system as previously described ( Figure 1 A,B) [ 21 ]. In LKB1 KO HT1080 cells, we found that cisplatin-induced p53 stabilization that indicates its activation was clearly attenuated, suggesting that LKB1 positively regulates cisplatin-induced p53 stabilization ( Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

“…All KO cells were generated using the CRISPR/Cas9 system, as described previously [ 21 , 58 ]. Guide RNAs (gRNAs) were designed to target a region in exon 1 of the hLKB1 gene (5′-GACTCGGAGACGCTGTGCAGG-3′), that in exon 1 of the hPRKAA1 (AMPKα1) gene (5′-GAAGCAGAAACACGACGGGC-3′), and that in exon 4 of the hPRKAA2 (AMPKα2) gene (5′-GGATTACTGTCATAGGCATA-3′), using CRISPRdirect ( accessed on 11 July 2017).…”

Section: Methodsmentioning

confidence: 99%

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The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin

Shimada

Yabuki

Noguchi

et al. 2022

IJMS

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Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin

Shimada

Yabuki

Noguchi

et al. 2022

IJMS

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“…TAK1 knockout cells were generated and characterized in the previous study [ 35 ]. All KO cells were generated using the CRISPR/Cas9 system as described previously [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK1

Shimada

Kudoh

Noguchi

et al. 2021

IJMS

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Receptor-interacting protein kinase 1 (RIPK1) is a key component of the tumor necrosis factor (TNF) receptor signaling complex that regulates both pro- and anti-apoptotic signaling. The reciprocal functions of RIPK1 in TNF signaling are determined by the state of the posttranslational modifications (PTMs) of RIPK1. However, the underlying mechanisms associated with the PTMs of RIPK1 are unclear. In this study, we found that RING finger protein 4 (RNF4), a RING finger E3 ubiquitin ligase, is required for the RIPK1 autophosphorylation and subsequent cell death. It has been reported that RNF4 negatively regulates TNF-α-induced activation of the nuclear factor-κB (NF-κB) through downregulation of transforming growth factor β-activated kinase 1 (TAK1) activity, indicating the possibility that RNF4-mediated TAK1 suppression results in enhanced sensitivity to cell death. However, interestingly, RNF4 was needed to induce RIPK1-mediated cell death even in the absence of TAK1, suggesting that RNF4 can promote RIPK1-mediated cell death without suppressing the TAK1 activity. Thus, these observations reveal the existence of a novel mechanism whereby RNF4 promotes the autophosphorylation of RIPK1, which provides a novel insight into the molecular basis for the PTMs of RIPK1.

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“…Bioimaging and quantification of intracellular ROS. Intracellular ROS was detected and quantified as described previously 39 . Briefly, after stimulation, cells seeded on a glass plate were treated with 10 μM DCFH-DA (Sigma) for 30 min, and intracellular ROS generation was observed using a Zeiss LSM800 laser confocal microscope (Carl Zeiss, Oberkochen, Germany) and the images were processed with Zen software.…”

Section: Cell Viability Assaymentioning

confidence: 99%

A comprehensive toxicological analysis of trans-fatty acids (TFAs) reveals a pro-apoptotic action specific to industrial TFAs counteracted by polyunsaturated FAs

Hirata

Kashiwabara

Nada

et al. 2023

Sci Rep

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Abstracttrans-Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon–carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.

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TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms

Cited by 18 publications

References 41 publications

The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin

The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin

The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK1

A comprehensive toxicological analysis of trans-fatty acids (TFAs) reveals a pro-apoptotic action specific to industrial TFAs counteracted by polyunsaturated FAs

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