Nit1 and Fhit tumor suppressor activities are additive

Sun, Jin; Okumura, Hiroshi; Yearsley, Martha; Frankel, Wendy L.; Fong, Louise Y.Y.; Druck, Teresa; Huebner, Kay

doi:10.1002/jcb.22207

Cited by 23 publications

(41 citation statements)

References 27 publications

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“…S12). Overall, this double localization of Nit1 is in agreement with the results of earlier studies (23,29) and is consistent with a role of the enzyme in recycling a side product of transaminases, which are abundant in both the cytosol and the mitochondria.…”

Section: Nit1 Localizes In Both the Cytosol And The Mitochondria Of Msupporting

confidence: 92%

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Peracchi

Veiga‐da‐Cunha

Kuhara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian gene Nit1 (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase (Nit2), the Nit1 protein does not hydrolyze efficiently α-ketoglutaramate (a known physiological substrate of Nit2), and its actual enzymatic function has so far remained a puzzle. In the present study, we demonstrate that both the mammalian Nit1 and its yeast ortholog are amidases highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group). We further show that Nit1-KO mutants of both human and yeast cells accumulate dGSH and the same compound is excreted in large amounts in the urine of Nit1-KO mice. Finally, we show that several mammalian aminotransferases (transaminases), both cytosolic and mitochondrial, can form dGSH via a common (if slow) side-reaction and provide indirect evidence that transaminases are mainly responsible for dGSH formation in cultured mammalian cells. Altogether, these findings delineate a typical instance of metabolite repair, whereby the promiscuous activity of some abundant enzymes of primary metabolism leads to the formation of a useless and potentially harmful compound, which needs a suitable "repair enzyme" to be destroyed or reconverted into a useful metabolite. The need for a dGSH repair reaction does not appear to be limited to eukaryotes: We demonstrate that Nit1 homologs acting as excellent dGSH amidases also occur in Escherichia coli and other glutathione-producing bacteria.metabolite repair | deaminated glutathione | amidase | aminotransferases

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Section: Nit1 Localizes In Both the Cytosol And The Mitochondria Of Msupporting

confidence: 92%

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Peracchi

Veiga‐da‐Cunha

Kuhara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies showed that Fhit knockout mice are more sensitive than wt mice to carcinogen‐induced epithelial tumors of the forestomach and esophagus 14, 26. Therefore, we expected that Fhit − / − mice would also develop more NMSC tumors compared to wt B6 mice, a strain with low predisposition for spontaneous skin tumors (http://www.informatics.jax.org/mtbwi/tumorFrequencyGrid.do).…”

Section: Resultsmentioning

confidence: 99%

“…B6 mice were from the Jackson Laboratory. Fhit − / − mice (~95% B6 genetic makeup) were generated as described 14, 26, backcrossed to B6 mice and carried as homozygous knockout mice; genotypes were confirmed before tumor induction. Mouse studies and experimentation were carried out according to protocols approved by the Ohio State University Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Sun

Shen²,

Schrock

et al. 2016

Cancer Medicine

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Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12‐dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn‐sufficient wild‐type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit‐deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer burdens would be reduced by Zn supplementation; (2) Fhit −/−(Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild‐type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2‐fold in Fhit −/− versus wild‐type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit −/− mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild‐type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn‐supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high‐risk human cohorts.

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“…Another candidate is Nitrilase1 (Nit1), a highly conserved protein that functions as a tumor suppressor (Sun et al, 2009). In Arabidopsis, changes in the polymer structure and the intracellular localization of Nit1 are closely associated with the transition from proliferation to differentiation (Doskocilová et al, 2013).…”

Section: How Do Oxylipin Carbonyls Initiate Pcd?mentioning

confidence: 99%

Lipid Peroxide-Derived Short-Chain Carbonyls Mediate Hydrogen Peroxide-Induced and Salt-Induced Programmed Cell Death in Plants

2015

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Lipid peroxide-derived toxic carbonyl compounds (oxylipin carbonyls), produced downstream of reactive oxygen species (ROS), were recently revealed to mediate abiotic stress-induced damage of plants. Here, we investigated how oxylipin carbonyls cause cell death. When tobacco (Nicotiana tabacum) Bright Yellow-2 (BY-2) cells were exposed to hydrogen peroxide, several species of short-chain oxylipin carbonyls [i.e. 4-hydroxy-(E)-2-nonenal and acrolein] accumulated and the cells underwent programmed cell death (PCD), as judged based on DNA fragmentation, an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei, and cytoplasm retraction. These oxylipin carbonyls caused PCD in BY-2 cells and roots of tobacco and Arabidopsis (Arabidopsis thaliana). To test the possibility that oxylipin carbonyls mediate an oxidative signal to cause PCD, we performed pharmacological and genetic experiments. Carnosine and hydralazine, having distinct chemistry for scavenging carbonyls, significantly suppressed the increase in oxylipin carbonyls and blocked PCD in BY-2 cells and Arabidopsis roots, but they did not affect the levels of ROS and lipid peroxides. A transgenic tobacco line that overproduces 2-alkenal reductase, an Arabidopsis enzyme to detoxify a,b-unsaturated carbonyls, suffered less PCD in root epidermis after hydrogen peroxide or salt treatment than did the wild type, whereas the ROS level increases due to the stress treatments were not different between the lines. From these results, we conclude that oxylipin carbonyls are involved in the PCD process in oxidatively stressed cells. Our comparison of the ability of distinct carbonyls to induce PCD in BY-2 cells revealed that acrolein and 4-hydroxy-(E)-2-nonenal are the most potent carbonyls. The physiological relevance and possible mechanisms of the carbonyl-induced PCD are discussed.

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Nit1 and Fhit tumor suppressor activities are additive

Cited by 23 publications

References 27 publications

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Lipid Peroxide-Derived Short-Chain Carbonyls Mediate Hydrogen Peroxide-Induced and Salt-Induced Programmed Cell Death in Plants

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