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  Redox signals at the ER-mitochondria interface control melanoma progression.

Zhang, X., Gibhardt, C. S., Will, T., Stanisz, H., Körbel, C., Mitkovski, M., et al. (2019). Redox signals at the ER-mitochondria interface control melanoma progression. The EMBO Journal, 38: e100871. doi:10.15252/embj.2018100871.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-4BFC-D Version Permalink: http://hdl.handle.net/21.11116/0000-0004-6361-F
Genre: Journal Article

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 Creators:
Zhang, X., Author
Gibhardt, C. S., Author
Will, T., Author
Stanisz, H., Author
Körbel, C., Author
Mitkovski, M., Author
Stejerean, I., Author
Cappello, S., Author
Pacheu‐Grau, D., Author
Dudek, J., Author
Tahbaz, N., Author
Mina, L., Author
Simmen, T., Author
Laschke, M. W., Author
Menger, M. D., Author
Schön, M. P., Author
Helms, V., Author
Niemeyer, B. A., Author
Rehling, P.1, Author              
Vultur, A., Author
Bogeski, I., Author more..
Affiliations:
1Max Planck Fellow Peter Rehling, ou_1298545              

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Free keywords: calcium; contact site; melanoma; mitochondria; redox
 Abstract: Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.

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Language(s): eng - English
 Dates: 2019-07-152019
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.15252/embj.2018100871
 Degree: -

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Title: The EMBO Journal
Source Genre: Journal
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Pages: 22 Volume / Issue: 38 Sequence Number: e100871 Start / End Page: - Identifier: -