| First Author | Bosso G | Year | 2024 |
| Journal | Cell Death Differ | Volume | 31 |
| Issue | 6 | Pages | 804-819 |
| PubMed ID | 38698060 | Mgi Jnum | J:349759 |
| Mgi Id | MGI:7658827 | Doi | 10.1038/s41418-024-01300-x |
| Citation | Bosso G, et al. (2024) Differential contribution for ERK1 and ERK2 kinases in BRAF(V600E)-triggered phenotypes in adult mouse models. Cell Death Differ 31(6):804-819 |
| abstractText | The BRAF gene is mutated in a plethora of human cancers. The majority of such molecular lesions result in the expression of a constitutively active BRAF variant (BRAF(V600E)) which continuously bolsters cell proliferation. Although we recently addressed the early effects triggered by BRAF(V600E)-activation, the specific contribution of ERK1 and ERK2 in BRAF(V600E)-driven responses in vivo has never been explored. Here we describe the first murine model suitable for genetically dissecting the ERK1/ERK2 impact in multiple phenotypes induced by ubiquitous BRAF(V600E)-expression. We unveil that ERK1 is dispensable for BRAF(V600E)-dependent lifespan shortening and for BRAF(V600E)-driven tumor growth. We show that BRAF(V600E)-expression provokes an ERK1-independent lymphocyte depletion which does not rely on p21(CIP1)-induced cell cycle arrest and is unresponsive to ERK-chemical inhibition. Moreover, we also reveal that ERK1 is dispensable for BRAF(V600E)-triggered cytotoxicity in lungs and that ERK-chemical inhibition abrogates some of these detrimental effects, such as DNA damage, in Club cells but not in pulmonary lymphocytes. Our data suggest that ERK1/ERK2 contribution to BRAF(V600E)-driven phenotypes is dynamic and varies dependently on cell type, the biological function, and the level of ERK-pathway activation. Our findings also provide useful insights into the comprehension of BRAF(V600E)-driven malignancies pathophysiology as well as the consequences in vivo of novel ERK pathway-targeted anti-cancer therapies. |
