Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish

SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC muta...
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Autor*in:	Corina Anastasaki [verfasserIn] Katherine A. Rauen [verfasserIn] E. Elizabeth Patton [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2012

Übergeordnetes Werk:	In: Disease Models & Mechanisms - The Company of Biologists, 2011, 5(2012), 4, Seite 546-552
Übergeordnetes Werk:	volume:5 ; year:2012 ; number:4 ; pages:546-552

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1242/dmm.008672

Katalog-ID:	DOAJ045149488

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520			\|a SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAFQ257R kinase-active allele and the BRAFG596V kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAFCFC mutations.
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allfieldsSound	10.1242/dmm.008672 doi (DE-627)DOAJ045149488 (DE-599)DOAJ0b7a895810d64f1381de7d6edf6cdeb0 DE-627 ger DE-627 rakwb eng RB1-214 Corina Anastasaki verfasserin aut Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAFQ257R kinase-active allele and the BRAFG596V kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAFCFC mutations. Medicine R Pathology Katherine A. Rauen verfasserin aut E. Elizabeth Patton verfasserin aut In Disease Models & Mechanisms The Company of Biologists, 2011 5(2012), 4, Seite 546-552 (DE-627)578531917 (DE-600)2451104-3 17548411 nnns volume:5 year:2012 number:4 pages:546-552 https://doi.org/10.1242/dmm.008672 kostenfrei https://doaj.org/article/0b7a895810d64f1381de7d6edf6cdeb0 kostenfrei http://dmm.biologists.org/content/5/4/546 kostenfrei https://doaj.org/toc/1754-8403 Journal toc kostenfrei https://doaj.org/toc/1754-8411 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_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 2012 4 546-552
language	English
source	In Disease Models & Mechanisms 5(2012), 4, Seite 546-552 volume:5 year:2012 number:4 pages:546-552
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authorswithroles_txt_mv	Corina Anastasaki @@aut@@ Katherine A. Rauen @@aut@@ E. Elizabeth Patton @@aut@@
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callnumber-first	R - Medicine
author	Corina Anastasaki
spellingShingle	Corina Anastasaki misc RB1-214 misc Medicine misc R misc Pathology Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
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topic_title	RB1-214 Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
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title	Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
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title_full	Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
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author_browse	Corina Anastasaki Katherine A. Rauen E. Elizabeth Patton
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title_sort	continual low-level mek inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
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title_auth	Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
abstract	SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAFQ257R kinase-active allele and the BRAFG596V kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAFCFC mutations.
abstractGer	SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAFQ257R kinase-active allele and the BRAFG596V kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAFCFC mutations.
abstract_unstemmed	SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAFQ257R kinase-active allele and the BRAFG596V kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAFCFC mutations.
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title_short	Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish
url	https://doi.org/10.1242/dmm.008672 https://doaj.org/article/0b7a895810d64f1381de7d6edf6cdeb0 http://dmm.biologists.org/content/5/4/546 https://doaj.org/toc/1754-8403 https://doaj.org/toc/1754-8411
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up_date	2024-07-04T01:50:48.941Z
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Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish

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