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PMID: 17369402 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis.

Genes & development ·Vol. 21 ·No. 6 ·2007-03-15 ·Pages 694-707

Shaw AT, Meissner A, Dowdle JA, Crowley D, Magendantz M, Ouyang C, Parisi T, Rajagopal J, Blank LJ, Bronson RT, Stone JR, Tuveson DA, Jaenisch R, Jacks T

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.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Base Sequence Embryo Loss/genetics Female Gene Expression Regulation, Developmental Gene Expression Regulation, Neoplastic Genes, ras Germ-Line Mutation Humans Intracellular Signaling Peptides and Proteins Lung/abnormalities,embryology,metabolism,pathology Lung Neoplasms/genetics,metabolism,pathology MAP Kinase Signaling System Membrane Proteins/deficiency,genetics,metabolism Mice Mice, Knockout Mice, Transgenic Pregnancy Protein Serine-Threonine Kinases RNA/genetics
Chemicals
Adaptor Proteins, Signal Transducing Intracellular Signaling Peptides and Proteins Membrane Proteins RNA Protein Serine-Threonine Kinases Spry2 protein, mouse
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Shaw Alice T
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston 02114, USA.
Meissner Alexander
Dowdle James A
Crowley Denise
Magendantz Margaret
Ouyang Chensi
Parisi Tiziana
Rajagopal Jayaraj
Blank Leah J
Bronson Roderick T
Stone James R
Tuveson David A
Jaenisch Rudolf
Jacks Tyler
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1526207
Published
2007-03-15
Pages
694-707
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC1820943
Subset
IM
Grants
NCI NIH HHS · 5K08CA111634-2 · United States
NCI NIH HHS · P30 CA014051 · United States
NCI NIH HHS · U01 CA084306 · United States
NCI NIH HHS · P30-CA14051 · United States
NCI NIH HHS · K08 CA111634 · United States
NCI NIH HHS · 5-U01-CA84306-06 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1101/gad.1526207 PMC Full Text View journal details
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