KrasP34R and KrasT58I 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...
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Autor*in:	Jasmine C. Wong [verfasserIn] Pedro A. Perez-Mancera [verfasserIn] Tannie Q. Huang [verfasserIn] Jangkyung Kim [verfasserIn] Joaquim Grego-Bessa [verfasserIn] Maria del pilar Alzamora [verfasserIn] Scott C. Kogan [verfasserIn] Amnon Sharir [verfasserIn] Susan H. Keefe [verfasserIn] Carolina E. Morales [verfasserIn] Denny Schanze [verfasserIn] Pau Castel [verfasserIn] Kentaro Hirose [verfasserIn] Guo N. Huang [verfasserIn] Martin Zenker [verfasserIn] Dean Sheppard [verfasserIn] Ophir D. Klein [verfasserIn] David A. Tuveson [verfasserIn] Benjamin S. Braun [verfasserIn] Kevin Shannon [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	Genetics

Übergeordnetes Werk:	In: JCI Insight - American Society for Clinical investigation, 2020, 5(2020), 21
Übergeordnetes Werk:	volume:5 ; year:2020 ; number:21

Links:	Link aufrufen Link aufrufen Journal toc

Katalog-ID:	DOAJ058213414

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allfields	(DE-627)DOAJ058213414 (DE-599)DOAJ3d9175f56bd4469b9994c659c5e9bbbc DE-627 ger DE-627 rakwb eng Jasmine C. Wong verfasserin aut KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Medicine R Pedro A. Perez-Mancera verfasserin aut Tannie Q. Huang verfasserin aut Jangkyung Kim verfasserin aut Joaquim Grego-Bessa verfasserin aut Maria del pilar Alzamora verfasserin aut Scott C. Kogan verfasserin aut Amnon Sharir verfasserin aut Susan H. Keefe verfasserin aut Carolina E. Morales verfasserin aut Denny Schanze verfasserin aut Pau Castel verfasserin aut Kentaro Hirose verfasserin aut Guo N. Huang verfasserin aut Martin Zenker verfasserin aut Dean Sheppard verfasserin aut Ophir D. Klein verfasserin aut David A. Tuveson verfasserin aut Benjamin S. Braun verfasserin aut Kevin Shannon verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 5(2020), 21 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:5 year:2020 number:21 https://doaj.org/article/3d9175f56bd4469b9994c659c5e9bbbc kostenfrei https://doi.org/10.1172/jci.insight.140495 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 21
spelling	(DE-627)DOAJ058213414 (DE-599)DOAJ3d9175f56bd4469b9994c659c5e9bbbc DE-627 ger DE-627 rakwb eng Jasmine C. Wong verfasserin aut KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Medicine R Pedro A. Perez-Mancera verfasserin aut Tannie Q. Huang verfasserin aut Jangkyung Kim verfasserin aut Joaquim Grego-Bessa verfasserin aut Maria del pilar Alzamora verfasserin aut Scott C. Kogan verfasserin aut Amnon Sharir verfasserin aut Susan H. Keefe verfasserin aut Carolina E. Morales verfasserin aut Denny Schanze verfasserin aut Pau Castel verfasserin aut Kentaro Hirose verfasserin aut Guo N. Huang verfasserin aut Martin Zenker verfasserin aut Dean Sheppard verfasserin aut Ophir D. Klein verfasserin aut David A. Tuveson verfasserin aut Benjamin S. Braun verfasserin aut Kevin Shannon verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 5(2020), 21 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:5 year:2020 number:21 https://doaj.org/article/3d9175f56bd4469b9994c659c5e9bbbc kostenfrei https://doi.org/10.1172/jci.insight.140495 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 21
allfields_unstemmed	(DE-627)DOAJ058213414 (DE-599)DOAJ3d9175f56bd4469b9994c659c5e9bbbc DE-627 ger DE-627 rakwb eng Jasmine C. Wong verfasserin aut KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Medicine R Pedro A. Perez-Mancera verfasserin aut Tannie Q. Huang verfasserin aut Jangkyung Kim verfasserin aut Joaquim Grego-Bessa verfasserin aut Maria del pilar Alzamora verfasserin aut Scott C. Kogan verfasserin aut Amnon Sharir verfasserin aut Susan H. Keefe verfasserin aut Carolina E. Morales verfasserin aut Denny Schanze verfasserin aut Pau Castel verfasserin aut Kentaro Hirose verfasserin aut Guo N. Huang verfasserin aut Martin Zenker verfasserin aut Dean Sheppard verfasserin aut Ophir D. Klein verfasserin aut David A. Tuveson verfasserin aut Benjamin S. Braun verfasserin aut Kevin Shannon verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 5(2020), 21 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:5 year:2020 number:21 https://doaj.org/article/3d9175f56bd4469b9994c659c5e9bbbc kostenfrei https://doi.org/10.1172/jci.insight.140495 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 21
allfieldsGer	(DE-627)DOAJ058213414 (DE-599)DOAJ3d9175f56bd4469b9994c659c5e9bbbc DE-627 ger DE-627 rakwb eng Jasmine C. Wong verfasserin aut KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Medicine R Pedro A. Perez-Mancera verfasserin aut Tannie Q. Huang verfasserin aut Jangkyung Kim verfasserin aut Joaquim Grego-Bessa verfasserin aut Maria del pilar Alzamora verfasserin aut Scott C. Kogan verfasserin aut Amnon Sharir verfasserin aut Susan H. Keefe verfasserin aut Carolina E. Morales verfasserin aut Denny Schanze verfasserin aut Pau Castel verfasserin aut Kentaro Hirose verfasserin aut Guo N. Huang verfasserin aut Martin Zenker verfasserin aut Dean Sheppard verfasserin aut Ophir D. Klein verfasserin aut David A. Tuveson verfasserin aut Benjamin S. Braun verfasserin aut Kevin Shannon verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 5(2020), 21 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:5 year:2020 number:21 https://doaj.org/article/3d9175f56bd4469b9994c659c5e9bbbc kostenfrei https://doi.org/10.1172/jci.insight.140495 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 21
allfieldsSound	(DE-627)DOAJ058213414 (DE-599)DOAJ3d9175f56bd4469b9994c659c5e9bbbc DE-627 ger DE-627 rakwb eng Jasmine C. Wong verfasserin aut KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Genetics Medicine R Pedro A. Perez-Mancera verfasserin aut Tannie Q. Huang verfasserin aut Jangkyung Kim verfasserin aut Joaquim Grego-Bessa verfasserin aut Maria del pilar Alzamora verfasserin aut Scott C. Kogan verfasserin aut Amnon Sharir verfasserin aut Susan H. Keefe verfasserin aut Carolina E. Morales verfasserin aut Denny Schanze verfasserin aut Pau Castel verfasserin aut Kentaro Hirose verfasserin aut Guo N. Huang verfasserin aut Martin Zenker verfasserin aut Dean Sheppard verfasserin aut Ophir D. Klein verfasserin aut David A. Tuveson verfasserin aut Benjamin S. Braun verfasserin aut Kevin Shannon verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 5(2020), 21 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:5 year:2020 number:21 https://doaj.org/article/3d9175f56bd4469b9994c659c5e9bbbc kostenfrei https://doi.org/10.1172/jci.insight.140495 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 21
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authorswithroles_txt_mv	Jasmine C. Wong @@aut@@ Pedro A. Perez-Mancera @@aut@@ Tannie Q. Huang @@aut@@ Jangkyung Kim @@aut@@ Joaquim Grego-Bessa @@aut@@ Maria del pilar Alzamora @@aut@@ Scott C. Kogan @@aut@@ Amnon Sharir @@aut@@ Susan H. Keefe @@aut@@ Carolina E. Morales @@aut@@ Denny Schanze @@aut@@ Pau Castel @@aut@@ Kentaro Hirose @@aut@@ Guo N. Huang @@aut@@ Martin Zenker @@aut@@ Dean Sheppard @@aut@@ Ophir D. Klein @@aut@@ David A. Tuveson @@aut@@ Benjamin S. Braun @@aut@@ Kevin Shannon @@aut@@
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author	Jasmine C. Wong
spellingShingle	Jasmine C. Wong misc Genetics misc Medicine misc R KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
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topic_title	KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice Genetics
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title	KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
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title_full	KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
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title_sort	krasp34r and krast58i mutations induce distinct rasopathy phenotypes in mice
title_auth	KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
url	https://doaj.org/article/3d9175f56bd4469b9994c659c5e9bbbc https://doi.org/10.1172/jci.insight.140495 https://doaj.org/toc/2379-3708
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KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice

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