Insights into Taurine Synthesis and Function Based on Studies with Cysteine Dioxygenase (CDO1) Knockout Mice

Stipanuk, Martha H.; Jurkowska, Halina; Roman, Heather B.; Niewiadomski, Julie; Hirschberger, Lawrence L.

doi:10.1007/978-3-319-15126-7_3

Cited by 14 publications

(10 citation statements)

References 28 publications

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“…To investigate the NRF2-dependent regulation of CDO1 protein in NSCLC, we generated a doxycycline-inducible lentiviral expression system to reintroduce GFP, CDO1 WT or a catalytically inactive CDO1 mutant (Y157F, Ye et al, 2007) at single copy into the panel of NRF2 LOW and NRF2 HIGH NSCLC cell lines (Figure 3D, Figure 3—figure supplement 2). The level of CDO1 protein expression in these cells was similar with the physiological Cdo1 levels in mouse lung and liver (Figure 3—figure supplement 2B), with liver being one of the highest CDO1-expressing tissues that is responsible for supplying TAU to the body (Stipanuk et al, 2015). We find that CDO1 accumulated to higher levels in NRF2 HIGH cells than NRF2 LOW , although accumulation was observed in many NRF2 LOW cell lines as well (Figure 3D).…”

Section: Resultssupporting

confidence: 56%

Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Kang

Torrente

Falzone

et al. 2019

eLife

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NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary murine cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite (SO32-), and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.

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Section: Resultssupporting

confidence: 56%

Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Kang

Torrente

Falzone

et al. 2019

eLife

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“…The level of CDO1 protein expression in these cells was similar with the physiological CDO1 levels in mouse lung and liver ( Figure S3D), with liver being one of the highest CDO1-expressing tissues that is responsible for supplying taurine to the body (Stipanuk et al, 2015). We find that CDO1 accumulated to higher levels in KEAP1 MUT cells than KEAP1 WT , although accumulation was observed in many KEAP1 WT cell lines as well ( Figure 3D).…”

Section: Cdo1 Is Preferentially Silenced In Keap1 Mutant Nsclc and Ansupporting

confidence: 69%

Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Kang

Torrente

Liu

et al. 2018

Preprint

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NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite, and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.

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“…In mammals, it undergoes up to 45-fold changes in concentration and up to 10-fold changes in catalytic efficiency (reviewed in [56]). Cellular CDO concentrations are tightly regulated by the rate of proteasomal degradation as controlled by polyubiquitination [57,58,59]. CDO concentrations can change up to 45-fold [60], multiplied by the potential 10-fold difference in catalytic efficiency [61], for a total potential change in CDO activity of up to 450-fold [40].…”

Section: Discussionmentioning

confidence: 99%

Taurine Biosynthesis in a Fish Liver Cell Line (ZFL) Adapted to a Serum-Free Medium

et al. 2017

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Although taurine has been shown to play multiple important physiological roles in teleosts, little is known about the molecular mechanisms underlying dietary requirements. Cell lines can provide useful tools for deciphering biosynthetic pathways and their regulation. However, culture media and sera contain variable taurine levels. To provide a useful cell line for the investigation of taurine homeostasis, an adult zebrafish liver cell line (ZFL) has been adapted to a taurine-free medium by gradual accommodation to a commercially available synthetic medium, UltraMEM™-ITES. Here we show that ZFL cells are able to synthesize taurine and be maintained in medium without taurine. This has allowed for the investigation of the effects of taurine supplementation on cell growth, cellular amino acid pools, as well as the expression of the taurine biosynthetic pathway and taurine transporter genes in a defined fish cell type. After taurine supplementation, cellular taurine levels increase but hypotaurine levels stay constant, suggesting little suppression of taurine biosynthesis. Cellular methionine levels do not change after taurine addition, consistent with maintenance of taurine biosynthesis. The addition of taurine to cells grown in taurine-free medium has little effect on transcript levels of the biosynthetic pathway genes for cysteine dioxygenase (CDO), cysteine sulfinate decarboxylase (CSAD), or cysteamine dioxygenase (ADO). In contrast, supplementation with taurine causes a 30% reduction in transcript levels of the taurine transporter, TauT. This experimental approach can be tailored for the development of cell lines from aquaculture species for the elucidation of their taurine biosynthetic capacity.

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Insights into Taurine Synthesis and Function Based on Studies with Cysteine Dioxygenase (CDO1) Knockout Mice

Cited by 14 publications

References 28 publications

Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Taurine Biosynthesis in a Fish Liver Cell Line (ZFL) Adapted to a Serum-Free Medium

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