JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer
E. Josue Ruiz, Linxiang Lan, Markus E. Diefenbacher, Eva M. Riising, Clive Da Costa, Atanu Chakraborty, Joerg D. Hoeck, Bradley Spencer‐Dene, Gavin Kelly, Jean‐Pierre David, Emma Nye, Julian Downward, Axel Behrens
Abstract
The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.