Regulation and Pathological Role of p53 in Cisplatin Nephrotoxicity

Jiang, Man; Dong, Zheng

doi:10.1124/jpet.108.139162

Cited by 138 publications

(133 citation statements)

References 108 publications

(145 reference statements)

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“…P53 Contributes to miR-375 Induction in Cisplatin Nephrotoxicity-P53 plays a critical role in cisplatin nephrotoxicity mainly by inducing downstream gene expression (22). Our previous study indicates that P53 is significantly induced in cisplatin nephrotoxicity (23), which correlates well with the pattern of mir-375 induction.…”

Section: Mir-375 Is Up-regulated In In Vivo and In Vitro Models Ofsupporting

confidence: 59%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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Edited by Joel GottesfeldNephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatininduced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatininduced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One upregulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-B attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-B in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1␤) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1␤ protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-B collaboratively induce miR-375 expression, which, in turn, represses HNF-1␤ activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

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Section: Mir-375 Is Up-regulated In In Vivo and In Vitro Models Ofsupporting

confidence: 59%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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“…hMSH2 Associates with ATR during Cisplatin TreatmentCisplatin treatment activates ATR to trigger a signaling cascade, leading to apoptosis (33,34); however, it is unclear how ATR is activated and regulated. To identify the regulators of ATR, we analyzed the proteins that associate with ATR during cisplatin treatment by BN-PAGE.…”

Section: Resultsmentioning

confidence: 99%

“…1) suggests that hMSH2 may regulate ATR and ATR-associated cellular response during cisplatin treatment. A notable cellular response following ATR activation during cisplatin treatment is apoptosis (30,(33)(34)(35)(36). To determine the role of hMSH2 in cisplatin-induced apoptosis, wild-type and hMSH2-deficient (hMSH2 Ϫ/Ϫ ) MEF cells were incubated with 20 M cisplatin treatment for 16 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cisplatin-induced DNA damage is not only responsible for its anti-cancer effects but also contributes to its side effects in normal tissues including nephrotoxicity in kidneys (30 -32). Cisplatin treatment results in ATR activation, which in turn phosphorylates and activates Chk2, followed by p53 activation leading to pro-apoptotic gene expression and cell death (30,(33)(34)(35)(36). However, it is unclear how ATR is activated during cisplatin treatment.…”

Section: Dna Damage Response (Ddr)mentioning

confidence: 99%

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hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis

Pabla

McIlhatton

et al. 2011

Journal of Biological Chemistry

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DNA damage response (DDR) activates a complex signaling network that triggers DNA repair, cell cycle arrest, and/or cell death. Depending on the type and severity of DNA lesion, DDR is controlled by "master" regulators including ATM and ATR protein kinases. Cisplatin, a major chemotherapy drug that cross-links DNA, induces ATR-dependent DDR, resulting in apoptosis. However, it is unclear how ATR is activated. To identify the key regulators of ATR, we analyzed the proteins that associate with ATR after cisplatin treatment by blue native-PAGE and co-immunoprecipitation. The mismatch repair protein hMSH2 was found to be a major ATR-binding protein.Functionally, ATR activation and its recruitment to nuclear foci during cisplatin treatment were attenuated, and DNA damage signaling, involving Chk2, p53, and PUMA-␣, was suppressed in hMSH2-deficient cells. ATR activation induced by the DNA methylating agent N-methyl-N-nitrosourea was also shown to be hMSH2-dependent. Intriguingly, hMSH2-mediated ATR recruitment and activation appeared independent of replication protein A, Rad17, and the Rad9-Hus1-Rad1 protein complex. Together the results support a hMSH2-dependent pathway of ATR activation and downstream Chk2/p53 signaling. DNA damage response (DDR)3 is essential for the maintenance of the integrity of the genome (1-5). As a complex multistep process, DDR involves the recognition of DNA damage, activation of DNA damage-responsive protein kinases, signal amplification by downstream protein kinases, and activation of the effector proteins that trigger various cellular processes. At low levels of DNA damage, activation of DDR results in cell cycle arrest and DNA repair. However, at higher doses, DDR signaling frequently results in cell death by apoptosis (1-5). The phosphoinositide 3-kinase-related protein kinases, ATM (ataxiatelangiectasia mutated) and ATR (ATM-and Rad3-related), are the key regulators of DDR (1-8). Once activated, ATM and ATR regulate an array of substrates including Chk1 and Chk2, which culminate in DNA repair, cell cycle arrest, and/or apoptosis. Although ATM is generally activated by doublestranded DNA breaks, ATR activation can result from different types of DNA lesion including single-stranded breaks, replication stress, base adducts, and DNA cross-links (8, 9). In the canonical model, ATR activation involves the recruitment of the ATR-ATRIP (ATR-interacting protein) and the Rad9-Hus1-Rad1 (9-1-1) protein complexes to the DNA damage site via replication protein A (RPA). As a result, the 9-1-1 complex brings topoisomerase-binding protein-1 (TopBP1, an ATR activator) close to ATR for ATR activation (1,5,8). However, alternative pathways of ATR activation may exist. For example, mismatch repair (MMR) proteins have been implicated in ATR activation under certain experimental conditions (10 -12).The MMR system is important for DNA replication and repair (13-18). In mammalian cells, MMR is composed of five MutS homologues (MSH) and four MutL homologue proteins. The function of MMR is to first recognize D...

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“…There may be a threshold effect of cell cycle inhibition, because other studies have shown that p53 can trigger tubular cell death in AKI. 57,58 Although the kidneys are known to have a remarkable reparative capacity, when injury is extensive or prolonged the repair in AKI may not be complete, leading to a maladaptive response that contributes to the late development of fibrosis and decline of renal function. 59,60 The cellular and molecular basis of this maladaptive response remains elusive, but it may involve transient cell cycle activation followed by cell cycle arrest.…”

Section: Receptorsmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

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180

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In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. Cellular and molecular mechanisms of AKI have been extensively investigated in a variety of experimental models, through which a number of candidate therapies for AKI have been identified. This article reviews the current evidence by dissecting the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, and using the example of ischemic AKI to describe our approach. Specifically, we reviewed the cellular and molecular epithelial cell targets that have been investigated in experimental models of ischemic AKI, and considered the clinical relevance of these models in human AKI and how such models might be improved to optimize translation into successful clinical trials. We have structured our review to answer two key questions:

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Regulation and Pathological Role of p53 in Cisplatin Nephrotoxicity

Cited by 138 publications

References 108 publications

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis

Cellular and Molecular Mechanisms of AKI

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