Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.
Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.
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DOI：
10.1093/hmg/ddp186
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发表时间：
2009-07-15
影响因子：
3.5
通讯作者：
Patton EE
中科院分区：
文献类型：
--
作者：
Anastasaki C;Estep AL;Marais R;Rauen KA;Patton EE
Ras/MAPK通路对人类发育至关重要，在大多数癌症的形成和进展中起着核心作用。出生时携带BRAF、MEK 1或MEK 2生殖系突变的儿童会患上心-面-皮肤（CFC）综合征，这是一种常染色体显性遗传综合征，其特征是独特的面部外观、心脏缺陷、皮肤和毛发异常以及智力迟钝。BRAF中CFC综合征突变促进激酶激活和激酶受损变体。CFC综合征具有进行性表型，并且MAPK途径的临床活性抑制剂的可用性提示了关于此类抑制剂在CFC综合征的治疗中是否可能是治疗有效的重要问题。为了研究CFC突变等位基因在体内的发育影响，我们在斑马鱼胚胎中表达了一组28个BRAF和MEK等位基因，以评估人类疾病等位基因和该途径的可用化学抑制剂的功能。我们发现，激酶激活和激酶受损的CFC突变等位基因促进同等的发育结果时，在早期发育和CFC-斑马鱼胚胎与FGF-MAPK通路的抑制剂治疗可以恢复正常的早期发育。重要的是，我们发现了一个发育窗口，在这个窗口中，使用MEK抑制剂治疗可以恢复胚胎的正常早期发育，而不会产生额外的、不必要的药物发育影响。
The Ras/MAPK pathway is critical for human development and plays a central role in the formation and progression of most cancers. Children born with germ-line mutations in BRAF, MEK1 or MEK2 develop cardio-facio-cutaneous (CFC) syndrome, an autosomal dominant syndrome characterized by a distinctive facial appearance, heart defects, skin and hair abnormalities and mental retardation. CFC syndrome mutations in BRAF promote both kinase-activating and kinase-impaired variants. CFC syndrome has a progressive phenotype, and the availability of clinically active inhibitors of the MAPK pathway prompts the important question as to whether such inhibitors might be therapeutically effective in the treatment of CFC syndrome. To study the developmental effects of CFC mutant alleles in vivo, we have expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. We find that both kinase-activating and kinase-impaired CFC mutant alleles promote the equivalent developmental outcome when expressed during early development and that treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway can restore normal early development. Importantly, we find a developmental window in which treatment with a MEK inhibitor can restore the normal early development of the embryo, without the additional, unwanted developmental effects of the drug.
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