Redox regulation of tumor suppressor PTEN in cell signaling

Zhang, Ying; Park, Jiyoung; Han, Seong Jeong; Yang, Sung Yeul; Yoon, Hyun Joong; Park, Iha; Woo, Hyun Ae; Lee, Seung Rock

doi:10.1016/j.redox.2020.101553

Cited by 66 publications

(61 citation statements)

References 104 publications

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“…This reduced activity of Trx caused by dimerization provides a mechanism by which Trx activity is transiently inhibited under the conditions of oxidative stress, providing more time for sensing and transmission of oxidative signals. This can be seen by redox regulation of cellular PTEN activity, which is restrained by the oxidation of active-site cysteine by reactive oxygen species (ROS) [ 33 ]. Recovery of its enzymatic activity predominantly depends on the availability of cellular thioredoxin (Trx) and peroxiredoxins (Prx), both are important players in cell signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Their dynamics are essential for protein functionality and regulation. The same study shows a tight association of the redox regulation of PTEN with Trx dimerization and Prx hyperoxidation, providing guidance for the identification of novel therapeutic targets[ 33 ]. In the literature, there is an evidence of a dimeric Trx-1 structure, but the existence of a quaternary structure of this protein has been debated.…”

Section: Discussionmentioning

confidence: 99%

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ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

et al. 2020

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The activity of Thioredoxin-1 (Trx-1) is adjusted by the balance of its monomeric, active and its dimeric, inactive state. The regulation of this balance is not completely understood. We have previously shown that the cytoplasmic domain of the transmembrane protein A D isintegrin A nd M etalloprotease 17 (ADAM17cyto) binds to Thioredoxin-1 (Trx-1) and the destabilization of this interaction favors the dimeric state of Trx-1. Here, we investigate whether ADAM17 plays a role in the conformation and activation of Trx-1. We found that disrupting the interacting interface with Trx-1 by a site-directed mutagenesis in ADAM17 (ADAM17cyto F730A ) caused a decrease of Trx-1 reductive capacity and activity. Moreover, we observed that ADAM17 overexpressing cells favor the monomeric state of Trx-1 while knockdown cells do not. As a result, there is a decrease of cell oxidant levels and ADAM17 sheddase activity and an increase in the reduced cysteine-containing peptides in intracellular proteins in ADAM17cyto overexpressing cells. A mechanistic explanation that ADAM17cyto favors the monomeric, active state of Trx-1 is the formation of a disulfide bond between Cys 824 at the C-terminal of ADAM17cyto with the Cys 73 of Trx-1, which is involved in the dimerization site of Trx-1. In summary, we propose that ADAM17 is able to modulate Trx-1 conformation affecting its activity and intracellular redox state, bringing up a novel possibility for positive regulation of thiol isomerase activity in the cell by mammalian metalloproteinases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

et al. 2020

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“…Exposure to H 2 O 2 for various times resulted in the formation of hyperoxidized Prxs. In Hela cells untreated with H 2 O 2 , the Prx I dimeric forms were predominantly observed since Prxs are considered as dimers in the absence of NEM [ 94 ]. The Prx I hyperoxidation levels reached a peak after 5 min of exposure and then gradually declined.…”

Section: Redox Regulation Of Pten By Peroxiredoxinsmentioning

confidence: 99%

“…The Prx I hyperoxidation levels reached a peak after 5 min of exposure and then gradually declined. Besides, the increase of oxidized PTEN levels showed similar kinetics to H 2 O 2 -induced Prx I hyperoxidation, and the transient hyperoxidation-induced suppression of Prx weakened H 2 O 2 -scavenging activity [ 94 ].…”

Section: Redox Regulation Of Pten By Peroxiredoxinsmentioning

confidence: 99%

Redox Regulation of PTEN by Peroxiredoxins

et al. 2021

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Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known as a tumor suppressor gene that is frequently mutated in numerous human cancers and inherited syndromes. PTEN functions as a negative regulator of PI3K/Akt signaling pathway by dephosphorylating phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) to phosphatidylinositol (4, 5)-bisphosphate (PIP2), which leads to the inhibition of cell growth, proliferation, cell survival, and protein synthesis. PTEN contains a cysteine residue in the active site that can be oxidized by peroxides, forming an intramolecular disulfide bond between Cys124 and Cys71. Redox regulation of PTEN by reactive oxygen species (ROS) plays a crucial role in cellular signaling. Peroxiredoxins (Prxs) are a superfamily of peroxidase that catalyzes reduction of peroxides and maintains redox homeostasis. Mammalian Prxs have 6 isoforms (I-VI) and can scavenge cellular peroxides. It has been demonstrated that Prx I can preserve and promote the tumor-suppressive function of PTEN by preventing oxidation of PTEN under benign oxidative stress via direct interaction. Also, Prx II-deficient cells increased PTEN oxidation and insulin sensitivity. Furthermore, Prx III has been shown to protect PTEN from oxidation induced by 15s-HpETE and 12s-HpETE, these are potent inflammatory and pro-oxidant mediators. Understanding the tight connection between PTEN and Prxs is important for providing novel therapies. Herein, we summarized recent studies focusing on the relationship of Prxs and the redox regulation of PTEN.

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“…Interestingly, 6 tumors, 4 of which were MSI-H, had either an insertion or a deletion within a poly(A 6 ) stretch in codons 321-323 [104]. PTEN deficiency could be a result of germline or somatic mutations, epigenetic silencing, abnormal transcriptional regulation, post-translational modifications, and protein-protein interactions [105,106]. The most frequently mutated genes in PTEN-defective solid tumors are well-known cancer genes, such as TP53, adenomatous polyposis coli (APC), titin (TTN), mucin 16 (MUC16), PIK3CA, axonemal central pair apparatus (HYDIN), BRAF, cadherin-1 (CDH1), and histone-lysine N-methyltransferase 2D (KMT2D), irrespective of the tumor type ( Figure 8).…”

Section: Inactivating Mutations Of Pten In Non-familial Solid Tumorsmentioning

confidence: 99%

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

Fusco

Sajjadi

Venetis

et al. 2020

Genes

102

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Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients’ clinical management, including risk assessment, diagnosis, prognostication, and treatment.

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Redox regulation of tumor suppressor PTEN in cell signaling

Cited by 66 publications

References 104 publications

ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

Redox Regulation of PTEN by Peroxiredoxins

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

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