Early differential responses elicited by BRAF(V600E) in adult mouse models

The BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAF(V600E)) which in turn sustains continuous cell proliferation. The study of BRAF(V600E) murine models has been mainly focused on the role of BRAF(V600E) in tumor development but little is known on the early molecular impact of BRAF(V600E) expression in vivo. Here, we study the immediate effects of acute ubiquitous BRAF(V600E) activation in vivo. We find that BRAF(V600E) elicits a rapid DNA damage response in the liver, spleen, lungs but not in thyroids. This DNA damage response does not occur at telomeres and is accompanied by activation of the senescence marker p21(CIP1) only in lungs but not in liver or spleen. Moreover, in lungs, BRAF(V600E) provokes an acute inflammatory state with a tissue-specific recruitment of neutrophils in the alveolar parenchyma and macrophages in bronchi/bronchioles, as well as bronchial/bronchiolar epithelium transdifferentiation and development of adenomas. Furthermore, whereas in non-tumor alveolar type II (ATIIs) pneumocytes, acute BRAF(V600E) induction elicits rapid p53-independent p21(CIP1) activation, adenoma ATIIs express p53 without resulting in p21(CIP1) gene activation. Conversely, albeit in Club cells BRAF(V600E)-mediated proliferative cue is more exacerbated compared to that occurring in ATIIs, such oncogenic stimulus culminates with p21(CIP1)-mediated cell cycle arrest and apoptosis. Our findings indicate that acute BRAF(V600E) expression drives an immediate induction of DNA damage response in vivo. More importantly, it also results in rapid differential responses of cell cycle and senescence-associated proteins in lung epithelia, thus revealing the early molecular changes emerging in BRAF(V600E)-challenged cells during tumorigenesis in vivo.