AcK-NFE2L2 and ATF4 bind the SLC7A11 gene

Stable Identifier
R-HSA-9761815
Type
Reaction [binding]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
AcK-NFE2L2 and ATF4 bind the SLC7A11 gene
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
SLC7A11 encodes one component of system xc-, a heterodimeric high affinity cystine-glutamate transporter that imports cystine in exchange for glutamate; the other protein component of the heterodimer is SLC3A2 (reviewed in Lewerenz et al, 2013). System xc- contributes to redox balance of the cell by increasing intracellular stores of cysteine, a limiting component in the synthesis of the key antioxidant glutathione (GSH). Depletion of GSH, for instance by inhibition of SLC7A11, causes lipid peroxidation and stimulates ferroptosis, a regulated form of cell death (reiewed in Chen et al, 2021; Kuang et al, 2020; Kajarabille and Latunde-Dada, 2019). NFE2L2 is a major transcriptional regulator of genes involved in mitigating oxidative stress, and as such effectively acts as a negative regulator of the ferroptosis pathway (reviewed in Baird and Yamamoto, 2020; Kuang et al, 2020; Chen et al, 2021). SLC7A11 expression is upregulated in response to NFE2L2 inducers and has been shown to be a direct downstream target of NFE2L2 and ATF4 (Ye et al, 2014; Ishii et al, 2000; Sasaki et al, 2002; Chen et al, 2017; Dong et al, 2020; reviewed in Kuang et al, 2020; Kajarabille and Latunde-Dada, 2019). CREBBP also co-immunoprecipitates with NFE2L2 at the SLC7A11, and CREBBP-dependent acetylation of NFE2L2 is required for promoter binding and transcriptional activation (Chen et al, 2017; Sun et al, 2009). The acetylation activity of CREBBP is inhibited by interaction between p14ARF and NFE2L2 at the SLC7A11 promoter (Chen et al, 2017).
Literature References
PubMed ID Title Journal Year
28985506 NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression

Baer, R, Gu, W, Erber, L, Chen, Y, Tavana, O, Chu, B, Chen, D

Mol Cell 2017
31597407 Programmed Cell-Death by Ferroptosis: Antioxidants as Mitigators

Latunde-Dada, GO, Kajarabille, N

Int J Mol Sci 2019
32284348 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Yamamoto, M, Baird, L

Mol Cell Biol 2020
22667998 The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities

Ganapathy, V, Smolders, I, Maher, P, Kalivas, PW, Lambros, M, Smith, SB, Pergande, M, Lewerenz, J, Methner, A, Gout, PW, Massie, A, Hewett, SJ, Huang, Y

Antioxid Redox Signal 2013
12235164 Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression

Wang, H, Yamamoto, M, Maebara, K, Tamba, M, Itoh, K, Sato, H, Sato, K, Kuriyama-Matsumura, K, Bannai, S, Sasaki, H

J Biol Chem 2002
10821856 Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages

Ishii, T, Sato, H, Yamamoto, M, Takahashi, S, Yanagawa, T, Bannai, S, Itoh, K, Katoh, Y

J Biol Chem 2000
33043019 Oxidative Damage and Antioxidant Defense in Ferroptosis

Tang, D, Liu, J, Kang, R, Kuang, F

Front Cell Dev Biol 2020
32601262 Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1

Xia, Y, Hu, R, Chai, D, Peng, J, Dong, H, Qiang, Z, Jiang, H

Aging (Albany NY) 2020
33462411 Cellular degradation systems in ferroptosis

Yu, C, Chen, X, Tang, D, Kroemer, G, Kang, R

Cell Death Differ 2021
25002527 Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition

Okada, T, Ohyama, C, Itoh, K, Mimura, J, Ye, P, Liu, T, Sato, H, Maruyama, A

Mol Cell Biol 2014
Participants
Input
Output
Participates
as an event of
Authored
Rothfels, K  (2021-10-08)
Reviewed
Cuadrado, A  (2022-02-23)
Created
Rothfels, K  (2022-01-15)
Cite Us!