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

E Josue Ruiz,Markus Elmar Diefenbacher,Axel Behrens,Atanu Chakraborty,Jean-Pierre David,Gavin Kelly,Joerg D Hoeck,Julian Downward,Clive Da Costa,Eva Madi Riising,Emma Nye,Linxiang Lan,Bradley Spencer-Dene

doi:10.1172/jci.insight.124985

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.

Highlights

Abnormal activation of the Ras signaling pathway is commonly found in human tumors
We investigated the importance of different AP-1 components in lung tumorigenesis, using lung-specific deletion of c-Jun or JunD combined with the inducible K-Ras–driven model of lung adenocarcinomas (LADCs) [5, 25]
We examined the correlation between JUN expression level and LADC patient survival

Summary

Introduction

Oncogenic mutations in Ras family proteins, such as K-RasG12D, constitutively activate growth factor signaling pathways and drive uncontrolled cell growth, proliferation, and invasiveness [1,2,3]. Since direct targeting of oncogenic Ras has proved extremely challenging, a detailed understanding of Ras downstream pathways is critical to enable targeted therapy for Ras-driven tumors. This need is especially pressing for lung cancer, a tumor type that often responds poorly to current treatments [6]. Oncogenic Ras signaling stimulates the AP-1 transcriptional activator family, which in turn controls a vast suite of genes involved in proliferation, migration, and apoptosis [7,8,9]. Each Jun protein can influence cell behavior in very different ways depending on context — for example, by promoting apoptosis in response to cellular stress or proliferation in response to growth factors [7,8,9]

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