JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer

• Published in: JCI insight Vol. 6; no. 13
• Main Authors: Ruiz, E Josue, Lan, Linxiang, Diefenbacher, Markus Elmar, Riising, Eva Madi, Da Costa, Clive, Chakraborty, Atanu, Hoeck, Joerg D, Spencer-Dene, Bradley, Kelly, Gavin, David, Jean-Pierre, Nye, Emma, Downward, Julian, Behrens, Axel
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.07.2021; American Society for Clinical investigation
• Subjects: Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Animals; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell biology; Gene Expression Regulation, Neoplastic - genetics; Gene Silencing; Genes, jun - genetics; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; MAP Kinase Kinase 7 - genetics; MAP Kinase Kinase 7 - metabolism; MAP Kinase Signaling System; Mice; Oncology; Phosphorylation; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; ras Proteins - metabolism; Transcription Factor AP-1 - metabolism; Oncology; Lung cancer; Cell Biology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.124985

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.