English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

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.

Early differential responses elicited by BRAFV600E in adult mouse models