1. Mutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis.
- Author
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Al Moussawi K, Chung K, Carroll TM, Osterburg C, Smirnov A, Lotz R, Miller P, Dedeić Z, Zhong S, Oti M, Kouwenhoven EN, Asher R, Goldin R, Tellier M, Murphy S, Zhou H, Dötsch V, and Lu X
- Subjects
- Animals, Mice, Cell Transformation, Neoplastic genetics, Inflammation genetics, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Tumor Microenvironment, MAP Kinase Kinase 4 metabolism, Transcription Factor AP-1 metabolism, Repressor Proteins metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Concurrent mutation of a RAS oncogene and the tumor suppressor p53 is common in tumorigenesis, and inflammation can promote RAS-driven tumorigenesis without the need to mutate p53. Here, we show, using a well-established mutant RAS and an inflammation-driven mouse skin tumor model, that loss of the p53 inhibitor iASPP facilitates tumorigenesis. Specifically, iASPP regulates expression of a subset of p63 and AP1 targets, including genes involved in skin differentiation and inflammation, suggesting that loss of iASPP in keratinocytes supports a tumor-promoting inflammatory microenvironment. Mechanistically, JNK-mediated phosphorylation regulates iASPP function and inhibits iASPP binding with AP1 components, such as JUND, via PXXP/SH3 domain-mediated interaction. Our results uncover a JNK-iASPP-AP1 regulatory axis that is crucial for tissue homeostasis. We show that iASPP is a tumor suppressor and an AP1 coregulator., Competing Interests: Declaration of interests X.L. is a scientific advisory board member of Oxford SimCell. T.M.C. is a founder, employee, and shareholder of a diagnostics company (Cleancard)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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