Sprouty-2 Regulates Oncogenic K-ras in Lung Development and Tumorigenesis

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2007 Mar 21

PMID 17369402

Citations 71

Authors

Alice T Shaw

Alexander Meissner

James A Dowdle

Denise Crowley

Margaret Magendantz

ChenSi OuYang

Tiziana Parisi

Jayaraj Rajagopal

Leah J Blank

Roderick T Bronson

James R Stone

David A Tuveson

Rudolf Jaenisch

Tyler Jacks

Affiliations

Soon will be listed here.

Abstract

Somatic activation of Ras occurs frequently in human cancers, including one-third of lung cancers. Activating Ras mutations also occur in the germline, leading to complex developmental syndromes. The precise mechanism by which Ras activation results in human disease is uncertain. Here we describe the phenotype of a mouse engineered to harbor a germline oncogenic K-rasG12D mutation. This mouse exhibits early embryonic lethality due to a placental trophoblast defect. Reconstitution with a wild-type placenta rescues the early lethality, but mutant embryos still succumb to cardiovascular and hematopoietic defects. 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 Sprouty-2 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 Sprouty-2 in vivo. Furthermore, in the context of K-rasG12D-mediated lung tumorigenesis, Sprouty-2 is also up-regulated and functions as a tumor suppressor to limit tumor number and overall tumor burden. These findings indicate that in the lung, Sprouty-2 plays a critical role in the regulation of oncogenic K-ras, and implicate counter-regulatory mechanisms in the pathogenesis of Ras-based disease.

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