@entity5743 regulates oncogenic XXXX in lung development and tumorigenesis.

@entity1 @entity2085 @entity19 @entity5 @entity984 @entity2 @entity245 @entity5743 @entity1583
Somatic activation of Ras occurs frequently in @entity1 @entity5 , including one-third of @entity2 . Activating Ras mutations also occur in the germline, leading to @entity245 . The precise mechanism by which Ras activation results in @entity1 disease is uncertain. Here we describe the phenotype of a @entity19 engineered to harbor a germline oncogenic K-rasG12D mutation. This @entity19 exhibits early @entity2085 due to a placental trophoblast defect. Reconstitution with a wild-type placenta rescues the early lethality, but mutant embryos still succumb to cardiovascular and @entity1583 . In addition, mutant embryos demonstrate a profound defect in lung branching morphogenesis associated with striking up-regulation of the Ras/mitogen-activated protein kinase (MAPK) antagonist @entity5743 and abnormal localization of MAPK activity within the lung epithelium. This defect can be significantly suppressed by lentiviral short hairpin RNA (shRNA)-mediated knockdown of @entity5743 in vivo. Furthermore, in the context of K-rasG12D-mediated lung tumorigenesis, @entity5743 is also up-regulated and functions as a @entity5 suppressor to limit @entity5 number and overall @entity5 burden. These findings indicate that in the lung, @entity5743 plays a critical role in the regulation of oncogenic @entity984 , and implicate counter-regulatory mechanisms in the pathogenesis of Ras-based disease.
