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
Inflammation ,p63 ,AP1/JNK ,skin cancer ,Settore BIO/11 ,MAP Kinase Kinase 4 ,iASPP ,Intracellular Signaling Peptides and Proteins ,inflammation-driven tumorigenesis ,General Biochemistry, Genetics and Molecular Biology ,Repressor Proteins ,Transcription Factor AP-1 ,Mice ,Cell Transformation, Neoplastic ,target selective transcription ,Tumor Microenvironment ,Animals ,Tumor Suppressor Protein p53 ,Molecular Developmental Biology ,CP: Cancer ,RAS - 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.
- Published
- 2022