Tumor Protein 53–Induced Nuclear Protein 1 Is a Major Mediator of p53 Antioxidant Function

Cano, Carla E.; Gommeaux, Julien; Pietri, Sylvia; Culcasi, Marcel; García, Stéphane; Seux, Mylène; Barelier, Sarah; Vasseur, Sophie; Spoto, Rose P.; Pébusque, Marie‐Josèphe; Dusetti, Nelson; Iovanna, Juan; Carrier, Alice

doi:10.1158/0008-5472.can-08-2320

Cited by 134 publications

(133 citation statements)

References 24 publications

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“…113 In addition, NRF2 is a downstream target of p53, which also drives the expression of other several genes with antioxidant functions like sestrin, GSH peroxidase, aldehyde dehydrogenase, GLS2, TIGAR, and tumor protein p53-inducible nuclear protein 1 (TP53INP1). 93,[114][115][116][117][118][119] Considering the central role of both NRF2 and p53 in modulating oxidative stress resistance in cancer, 120 further studies are required to establish their contribute in RMS.…”

Section: Oxidative Stress Pathwaysmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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Section: Oxidative Stress Pathwaysmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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“…p53-deficient cells show intracellular accumulation of ROS, excessive oxidation of DNA, increased mutation rate, which can all be prevented by incubation of these cells with antioxidant N-acetylcysteine (Cano et al, 2009). This characteristic can be related to another welldescribed function of DJ-1: its ability to scavenge oxidants during oxidative stress (Kahle et al, 2009).…”

Section: Dj-1/p53 Connection During Cell Transformation S Vasseur Et Almentioning

confidence: 99%

Consequences of DJ-1 upregulation following p53 loss and cell transformation

et al. 2011

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p53 is a tumor suppressor that responds to various stress signals by initiating cell-cycle arrest, senescence and apoptosis. Mutations of the p53 gene are found in over 50% of human tumors, highlighting the importance of p53 in tumor suppression. Numerous studies have reported on the interactions between p53, IGF-1-AKT and mTOR pathways as potentially explaining some of the tumor suppressive activities of p53. To further understand the basis of these interactions, we analyzed the involvement of DJ-1, an oncogene known to drive AKT-mediated cell survival, in the p53-AKT axis. In this study, we show that DJ-1 and p53 are tightly 'linked': p53 prevents the accumulation of DJ-1 protein, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. Interestingly, this increase in DJ-1 level is only observed when p53 loss is accompanied by transformation of cells. Moreover, DJ-1 seems to be required for the enhanced activation of AKT observed in p53-deficient cells. Such observation confers a new property to DJ-1 associated to transforming-process to its oncogenic ability to drive AKT activation. We also show that DJ-1 is necessary for p53 activation following oxidative stress, suggesting the existence of a finely regulated loop between these two proteins in transformed cells. Finally, we demonstrate that in the absence of p53, DJ-1 is stabilized by ROS accumulation, and surprisingly seems to be required for this high intracellular ROS production. These data offer new insights into the regulation of DJ-1 and suggest that DJ-1 is a target of p53. Importantly, our study highlights that during transformation, DJ-1 is having a key role in the p53-regulated AKT pathway and p53-driven oxidative-stress response.

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“…15,16 Interestingly, the role of TP53INP1 as a tumor suppressor is associated with its ability to enhance the p53 antioxidant function. 17 In accordance, TP53INP1 transcriptional induction upon oxidative stress is strictly dependent on p53, and TP53INP1-deficient cells accumulate more intracellular reactive oxygen species (ROS) than wild-type cells. This ROS accumulation is associated with a decreased expression of several p53 targets, including p21, Sesn2, PUMA and Bax.…”

mentioning

confidence: 94%

“…In summary, TP53INP1 is a major regulator of p53 response to oxidative stress. 17 Post-translational modifications of proteins by ubiquitin and ubiquitin-like proteins have emerged since the last years as major regulators of proteins activity, localization and interactions. [18][19][20] Ubiquitin-like conjugations are highly dynamic modifications, and multiple isopeptidases are able to remove the modifier from its substrate.…”

mentioning

confidence: 99%

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

et al. 2014

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Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcriptional activity is enhanced by the oxidative stress-induced SUMOylation of TP53INP1 at lysine 113. This SUMOylation is mediated by PIAS3 and CBX4, two SUMO ligases especially related to the p53 activation upon DNA damage. Importantly, this modification is reversed by three SUMO1-specific proteases SENP1, 2 and 6. Moreover, TP53INP1 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions. TP53INP1 mutation at lysine 113 prevents the pro-apoptotic, antiproliferative and antioxidant effects of TP53INP1 by impairing the p53 response on its target genes p21, Bax and PUMA. We conclude that TP53INP1 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress. Cell Death and Differentiation (2014) 21, 1107-1118; doi:10.1038/cdd.2014.28; published online 7 March 2014Maintaining homeostasis in response to the broad range of intrinsic and extrinsic aggressions is a challenge for cells. Cellular outcomes are varied and involve cell-cycle arrest, apoptosis, DNA repair, autophagy, senescence, antioxidant activity, cell migration, differentiation, embryo implantation, metabolism and angiogenesis.1-9 An inadequate cell response can lead to cellular transformation and cancer initialization. Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a p53 cofactor. The gene TP53INP1 encodes for two protein isoforms generated by alternative splicing, named TP53INP1a and TP53INP1b. TP53INP1 is a p53 target gene and its expression is induced in response to several physical and chemical stresses.10-12 TP53INP1 directly interacts with p53 and also binds kinases, such as HIPK2 and PKCd, which modulate p53 transcriptional activity by phosphorylation, thereby creating a positive feedback loop between p53 and TP53INP1.13,14 Our laboratory demonstrated the role of TP53INP1 as a tumor suppressor as TP53INP1-deficient mice present an increased susceptibility to tumor development. Moreover, TP53INP1 expression is lost at very early steps of pancreatic carcinogenesis due to miR155 activity and, when its expression is restored in pancreatic cancer cells, it suppresses growth of xenograft tumors by favoring apoptotic cell death. 15,16 Interestingly, the role of TP53INP1 as a tumor suppressor is associated with its ability to enhance the p53 antioxidant function. 17 In accordance, TP53INP1 transcriptional induction upon oxidative stress is strictly dependent on p53, and TP53INP1-deficient cells accumulate more intracellular reactive oxygen species (ROS) than wild-type cells. This ROS accumulation is...

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Tumor Protein 53–Induced Nuclear Protein 1 Is a Major Mediator of p53 Antioxidant Function

Cited by 134 publications

References 24 publications

Uncovering metabolism in rhabdomyosarcoma

Uncovering metabolism in rhabdomyosarcoma

Consequences of DJ-1 upregulation following p53 loss and cell transformation

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

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