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dc.contributor.authorWong, Jasmine C
dc.contributor.authorPerez-Mancera, Pedro A
dc.contributor.authorHuang, Tannie Q
dc.contributor.authorKim, Jangkyung
dc.contributor.authorGrego-Bessa, Joaquim 
dc.contributor.authorDel Pilar Alzamora, Maria
dc.contributor.authorKogan, Scott C
dc.contributor.authorSharir, Amnon
dc.contributor.authorKeefe, Susan H
dc.contributor.authorMorales, Carolina E
dc.contributor.authorSchanze, Denny
dc.contributor.authorCastel, Pau
dc.contributor.authorHirose, Kentaro
dc.contributor.authorHuang, Guo N
dc.contributor.authorZenker, Martin
dc.contributor.authorSheppard, Dean
dc.contributor.authorKlein, Ophir D
dc.contributor.authorTuveson, David A
dc.contributor.authorBraun, Benjamin S
dc.contributor.authorShannon, Kevin
dc.identifier.citationJCI Insight. 2020; 5(21):140495es_ES
dc.description.abstractSomatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.es_ES
dc.description.sponsorshipThis work was supported by National Institutes of Health/National Cancer Center grants R37 CA72614 and U54CA196519 (to K.S.); R50CA211452 (to J.C.W.), R35-DE026602 (to O.D.K.), K08-DE026219 (to A.S.); and P30CA082103 Cancer Center Support Grant to the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. K.S. is an American Cancer Society Research Professor. J.G-B is funded by Programa de Atracción de Talento from Comunidad de Madrid. P.C. is a fellow of the Jane Coffin Childs Memorial Fund. K.H. is a fellow of the Japan Society for the Promotion of Science Overseas Research Fellowships.es_ES
dc.publisherAmerican Society for Clinical Investigation (ASCI) es_ES
dc.titleKrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderNational Institutes of Health (Estados Unidos) 
dc.contributor.funderNational Cancer Center (Estados Unidos) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderJapan Society for the Promotion of Science (Japón) 
dc.identifier.journalJCI insightes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Señalización Intercelular durante el Desarrollo y la Enfermedad Cardiovasculares_ES
dc.rights.accessRightsopen accesses_ES

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