Abstract
Somatic 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.
Original language | American English |
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Article number | e140495 |
Journal | JCI insight |
Volume | 5 |
Issue number | 21 |
DOIs | |
State | Published - 5 Nov 2020 |
Externally published | Yes |
Bibliographical note
Funding Information:We thank members of the Shannon lab for helpful discussions and for providing advice. We thank X. Zou for assistance with blastocyst injection to generate the KrasLSL-P34R/+ and KrasLSL-T58I/+ strains. We also thank T. Huynh from the MicroPET/CT, MicroSPECT/CT, Optical Imaging Core Facility and Nicholas Szeto from the Skeletal Biology and Biomechanics Core for their expertise in and technical support of μ-CT analysis. We thank Jennifer Bolen from the Biorepository and Tissue Biomarker Technology Core for helpful advice on and technical support of tissue processing and histological detection. This work was supported by NIH/National Cancer Institute grants R37 CA72614 and U54CA196519 (to KS), R50 CA211452 (to JCW), R35-DE026602 (to ODK), and K08-DE026219 (to AS) and NIH/National Cancer Center Support Grant P30 CA082103 to the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. KS is an American Cancer Society Research Professor. JGB is funded by Programa de Atracción de Talento from Comunidad de Madrid. PC is a fellow of the Jane Coffin Childs Memorial Fund. KH is a fellow of the Japan Society for the Promotion of Science Overseas Research Fellowships.
Publisher Copyright:
Copyright: © 2020, Wong et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.