Glutathione Peroxidase 4 Is Required for Maturation of Photoreceptor Cells

Ueta, Takashi; Inoue, Tatsuya; Furukawa, Takahisa; Tamaki, Yasuhiro; Nakagawa, Yasuhito; Imai, Hideki; Yanagi, Yasuo

doi:10.1074/jbc.m111.335174

Cited by 112 publications

(73 citation statements)

References 30 publications

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“…Systemic deletion of Gpx4 in mice causes embryonic lethality, which was not observed when other Gpx genes were deleted (Ran et al, 2004), suggesting a unique role for Gpx4 in physiology. Four groups independently created conditional Gpx4 knockout mice and analyzed the cell death mechanisms after Gpx4 inhibition (Seiler et al, 2008; Sengupta et al, 2013; Ueta et al, 2012; Yoo et al, 2012). Lipid peroxidation was observed in all knockout models, highlighting the importance of Gpx4 for protecting cells from detrimental effects of lipid peroxides.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Ferroptotic Cancer Cell Death by GPX4

Yang

Sriramaratnam

Welsch

et al. 2014

Cell

5,258

128

4,934

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SUMMARY Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosisinducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.

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Section: Discussionmentioning

confidence: 99%

Regulation of Ferroptotic Cancer Cell Death by GPX4

Yang

Sriramaratnam

Welsch

et al. 2014

Cell

5,258

128

4,934

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“…70 A recent study has shown that GPx4 plays an important protective role for photoreceptor cells against oxidative stress. 71 GPx6 is a close homolog of plasma GPx3. Compared to other GPx proteins, GPx6 was identified rather late because its mouse and rat orthologs had Cys in place of SeCys.…”

Section: Glutathione Peroxidasesmentioning

confidence: 99%

Selenium biochemistry and its role for human health

Roman¹,

Jitaru²,

Barbante³

2014

Metallomics

654

451

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Despite its very low level in humans, selenium plays an important and unique role among the (semi)metal trace essential elements because it is the only one for which incorporation into proteins is genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five selenoproteins have been identified so far in the human proteome. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic effect for human diseases. This review summarizes the most recent findings on the biochemistry of active selenium species in humans, and addresses the latest evidence on the link between selenium intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the interpretation of biochemical mechanisms rather than epidemiological/observational data. In this context, the review includes the following sections: (1) brief introduction; (2) general nutritional aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of human diseases.

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“…9 Of importance, Gpx4 is the only glutathione peroxidase known to be essential for embryonic development. 10,11 Moreover, Gpx4 controls caspase-independent cell death in neurons, 12 photoreceptor cells, 13 and T cells. 14 Ferroptosis is a nonapoptotic form of cell death involving the production of iron-dependent ROS.…”

Section: Introductionmentioning

confidence: 99%