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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. [Display omitted] • iASPP is a tumor suppressor of DMBA/TPA-driven mouse skin tumorigenesis • iASPP controls selective transcription of AP1 and p63 target genes in keratinocytes • JNK activation disrupts iASPP-JunD complexes that are mediated by PxxP/SH3 binding • iASPP is a regulator of the AP1 signaling pathway Al Moussawi et al. show that iASPP, a known p53 inhibitor, suppresses inflammation-driven skin tumorigenesis in vivo. Mechanistically, iASPP binds JunD via PxxP/SH3 interaction and forms a JNK-iASPP-AP1 axis that selectively represses the expression of a subset of AP1 and p63 target genes involved in skin differentiation and inflammation. [ABSTRACT FROM AUTHOR]