Cargando…

Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice

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 can...

Descripción completa

Detalles Bibliográficos
Autores principales: Wong, Jasmine C., Perez-Mancera, Pedro A., Huang, Tannie Q., Kim, Jangkyung, Grego-Bessa, Joaquim, del pilar Alzamora, Maria, Kogan, Scott C., Sharir, Amnon, Keefe, Susan H., Morales, Carolina E., Schanze, Denny, Castel, Pau, Hirose, Kentaro, Huang, Guo N., Zenker, Martin, Sheppard, Dean, Klein, Ophir D., Tuveson, David A., Braun, Benjamin S., Shannon, Kevin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710308/
https://www.ncbi.nlm.nih.gov/pubmed/32990679
http://dx.doi.org/10.1172/jci.insight.140495
_version_ 1783617920975241216
author Wong, Jasmine C.
Perez-Mancera, Pedro A.
Huang, Tannie Q.
Kim, Jangkyung
Grego-Bessa, Joaquim
del pilar Alzamora, Maria
Kogan, Scott C.
Sharir, Amnon
Keefe, Susan H.
Morales, Carolina E.
Schanze, Denny
Castel, Pau
Hirose, Kentaro
Huang, Guo N.
Zenker, Martin
Sheppard, Dean
Klein, Ophir D.
Tuveson, David A.
Braun, Benjamin S.
Shannon, Kevin
author_facet Wong, Jasmine C.
Perez-Mancera, Pedro A.
Huang, Tannie Q.
Kim, Jangkyung
Grego-Bessa, Joaquim
del pilar Alzamora, Maria
Kogan, Scott C.
Sharir, Amnon
Keefe, Susan H.
Morales, Carolina E.
Schanze, Denny
Castel, Pau
Hirose, Kentaro
Huang, Guo N.
Zenker, Martin
Sheppard, Dean
Klein, Ophir D.
Tuveson, David A.
Braun, Benjamin S.
Shannon, Kevin
author_sort Wong, Jasmine C.
collection PubMed
description 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 Kras(LSL-P34R)and Kras(LSL-T58I) knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of Kras(T58I) 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 Kras(P34R) 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 Kras(P34R) and Kras(T58I) 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.
format Online
Article
Text
id pubmed-7710308
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-77103082020-12-04 Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice Wong, Jasmine C. Perez-Mancera, Pedro A. Huang, Tannie Q. Kim, Jangkyung Grego-Bessa, Joaquim del pilar Alzamora, Maria Kogan, Scott C. Sharir, Amnon Keefe, Susan H. Morales, Carolina E. Schanze, Denny Castel, Pau Hirose, Kentaro Huang, Guo N. Zenker, Martin Sheppard, Dean Klein, Ophir D. Tuveson, David A. Braun, Benjamin S. Shannon, Kevin JCI Insight Research Article 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 Kras(LSL-P34R)and Kras(LSL-T58I) knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of Kras(T58I) 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 Kras(P34R) 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 Kras(P34R) and Kras(T58I) 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. American Society for Clinical Investigation 2020-11-05 /pmc/articles/PMC7710308/ /pubmed/32990679 http://dx.doi.org/10.1172/jci.insight.140495 Text en © 2020 Wong et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Wong, Jasmine C.
Perez-Mancera, Pedro A.
Huang, Tannie Q.
Kim, Jangkyung
Grego-Bessa, Joaquim
del pilar Alzamora, Maria
Kogan, Scott C.
Sharir, Amnon
Keefe, Susan H.
Morales, Carolina E.
Schanze, Denny
Castel, Pau
Hirose, Kentaro
Huang, Guo N.
Zenker, Martin
Sheppard, Dean
Klein, Ophir D.
Tuveson, David A.
Braun, Benjamin S.
Shannon, Kevin
Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice
title Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice
title_full Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice
title_fullStr Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice
title_full_unstemmed Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice
title_short Kras(P34R) and Kras(T58I) mutations induce distinct RASopathy phenotypes in mice
title_sort kras(p34r) and kras(t58i) mutations induce distinct rasopathy phenotypes in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710308/
https://www.ncbi.nlm.nih.gov/pubmed/32990679
http://dx.doi.org/10.1172/jci.insight.140495
work_keys_str_mv AT wongjasminec krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT perezmancerapedroa krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT huangtannieq krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT kimjangkyung krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT gregobessajoaquim krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT delpilaralzamoramaria krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT koganscottc krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT shariramnon krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT keefesusanh krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT moralescarolinae krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT schanzedenny krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT castelpau krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT hirosekentaro krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT huangguon krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT zenkermartin krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT shepparddean krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT kleinophird krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT tuvesondavida krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT braunbenjamins krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice
AT shannonkevin krasp34randkrast58imutationsinducedistinctrasopathyphenotypesinmice