Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1

Saitoh, Masao

doi:10.1093/emboj/17.9.2596

Cited by 2,209 publications

(1,942 citation statements)

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“…Trx is well-known for its anti-apoptotic effects by the inhibition of the ASK1 pathway [14,20,43–45], and reduced apoptosis could be one of the contributing factors for cancer onset/progression [46]. Our current and previous studies also show that Trx1 overexpression in mice inhibits the ASK1 pathway, which could facilitate cancer growth in old animals.…”

Section: Discussionsupporting

confidence: 65%

“…Both Trx1 and 2 play essential biological roles in mammals. Some of the physiologically important roles of Trx include: 1) acting as a hydrogen donor for enzymes involved in reductive reactions [3–8]; 2) maintaining a reduced environment in cells [9]; 3) controlling protein (especially transcription factors) function via the redox state [10–12] and the expression of target genes; 4) protecting cells and tissues from oxidative stress [13]; and 5) having anti-apoptotic effects through the inhibition of the ASK [14] and mitochondrial pathways [15]. The essential biological roles of Trx were further supported by two studies which demonstrated that mice null for either Trx1 or Trx2 were embryonically lethal [16,17].…”

Section: Introductionmentioning

confidence: 99%

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Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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We examined the effects of continuous overexpression of thioredoxin (Trx) 1 on aging in Trx1 transgenic mice [Tg(TXN)+/0]. This study was conducted to test whether increased thioredoxin expression over the lifespan in mice would alter aging and age-related pathology because our previous study demonstrated that Tg(act-TXN)+/0 mice had no significant maximum life extension, possibly due to the use of actin as a promoter, which may have resulted in loss of Trx1 overexpression during aging. To test this hypothesis, we generated new Trx1 transgenic mice using a fragment of the human genome containing the TXN gene with an endogenous promoter to ensure continuous overexpression of Trx1 throughout the lifespan. Universal overexpression of Trx1 was observed, and Trx1 overexpression was maintained during aging (up to 22–24 months old) in the Tg(TXN)+/0 mice. The levels of Trx1 are significantly higher (approximately 4 to 31 fold) in all of the tissues examined in the Tg(TXN)+/0 mice compared to the wild-type (WT) littermates. The overexpression of Trx1 did not cause any changes in the levels of Trx2, glutaredoxin, glutathione, or other major antioxidant enzymes. The survival study demonstrated that male Tg(TXN)+/0 mice slightly extended the earlier part of the lifespan compared to WT littermates, but no significant life extension was observed over the lifespan. The cross-sectional pathological analysis (22–25 months old) showed that Tg(TXN)+/0 mice had a significantly higher severity of lymphoma and more tumor burden than WT mice, which was associated with the suppression of the apoptosis signal-regulating kinase 1 (ASK1) pathway. Our findings suggest that the increased levels of Trx1 over the lifespan in Tg(TXN)+/0 mice showed some beneficial effects (slight extension of lifespan) in the earlier part of life but had no significant effects on median or maximum lifespans, and increased Trx1 levels enhanced tumor development in old mice.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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“…While TRAF-2 is required for the activation of JNK, FADD is required for caspase activation, and RIP and Hsp90 are important for the activation of NF-κB. TRAF2 can bind to and activate apoptosis signal-regulating kinase (ASK1), an important regulator of apoptosis [166,167]. Through a genetic screen, Trx was identified as an interacting partner of ASK1, and was demonstrated to regulate ASK1 function via a redox mechanism.…”

Section: Regulation Of Molecular Adaptors and Chaperonesmentioning

confidence: 99%

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

Janssen–Heininger¹,

Mossman²,

Heintz³

et al. 2008

Free Radical Biology and Medicine

705

652

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“…Among the signaling proteins (and their critical cysteines) that have been well characterized are the PTPs, PTP1B (cys 215 ) (26,27,(34)(35)(36), low molecular weight PTP (cys12,17) (37-39) and Srchomology 2 domain-containing PTP (SHP-2) (40), the small G protein, Ras (cys 118 ) (41)(42)(43)(44), the large G proteins, G i (cys 267 ) and G o (cys 326 ) (45) and the lipid phosphatase, phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In addition, as mentioned above, in its reduced form Trx binds and inhibits ASK1 and possibly other signaling proteins as well (46)(47)(48)(49)(50)(51)(52)(53). When oxidized by formation of a disulfide between the two cysteines in its active site, Trx dissociates from ASK1, allowing it to become activated (46)(47)(48)(49)(50)(51)(52)(53) (Figure 1).…”

Section: A Signaling Proteins In Which Critical Cysteines Are Modifiedmentioning

confidence: 99%

“…In addition, as mentioned above, in its reduced form Trx binds and inhibits ASK1 and possibly other signaling proteins as well (46)(47)(48)(49)(50)(51)(52)(53). When oxidized by formation of a disulfide between the two cysteines in its active site, Trx dissociates from ASK1, allowing it to become activated (46)(47)(48)(49)(50)(51)(52)(53) (Figure 1). Also, GSTΠ inhibits c-Jun-N-terminal kinase (JNK) but dissociates and allows JNK activation when its critical active site cysteine is oxidized (54)(55)(56).…”

Section: A Signaling Proteins In Which Critical Cysteines Are Modifiedmentioning

confidence: 99%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

219

165

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During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

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Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1

Cited by 2,209 publications

References 58 publications

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

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