biostudies-literatureUnknown41(3)Al Moussawi KNational Institute for Health Research (NIHR)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.Cell reports111503https://www.ebi.ac.uk/biostudies/studies/S-EPMC9597577biostudies-literatureMutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis.PMC9597577Lu XCarroll TMChung KMiller PAsher RAl Moussawi KGoldin RZhong SKouwenhoven ENLotz ROsterburg CSmirnov ADedeic ZTellier MMurphy SZhou HDotsch VOti MfalseMutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis.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.2022-01-01T00:00:00Z2022 Oct2024-10-19T01:41:38.925Z2024-10-19T01:41:38.925ZS-EPMC95975773626100010.1016/j.celrep.2022.111503