Mutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis

Cell Rep. 2022 Oct 18;41(3):111503. doi: 10.1016/j.celrep.2022.111503.

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.

Keywords: AP1/JNK; CP: Cancer; RAS; iASPP; inflammation-driven tumorigenesis; p63; skin cancer; target selective transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Inflammation / genetics
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Repressor Proteins* / metabolism
  • Transcription Factor AP-1 / metabolism
  • Tumor Microenvironment
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • MAP Kinase Kinase 4
  • Transcription Factor AP-1
  • Ppp1r13l protein, mouse