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学科主题口腔医学
Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation
Goodwin, Alice F.1,2; Tidyman, William E.1,2; Jheon, Andrew H.1,2; Sharir, Amnon1,2; Zheng, Xu1,2,6; Charles, Cyril1,2; Fagin, James A.7; McMahon, Martin3; Diekwisch, Thomas G. H.8; Ganss, Bernhard9; Rauen, Katherine A.3,4,5; Klein, Ophir D.1,2,3,4,5
刊名HUMAN MOLECULAR GENETICS
2014-02-01
DOI10.1093/hmg/ddt455
23期:3页:682-692
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology ; Genetics & Heredity
研究领域[WOS]Biochemistry & Molecular Biology ; Genetics & Heredity
关键词[WOS]FACIO-CUTANEOUS SYNDROME ; STEM-CELLS ; AMELOGENESIS IMPERFECTA ; DEVELOPMENTAL DEFECTS ; GERMLINE MUTATIONS ; NOONAN SYNDROME ; MOUSE INCISOR ; HRAS ; POLARITY ; PATHWAY
英文摘要

RASopathies are syndromes caused by gain-of-function mutations in the Ras signaling pathway. One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities. We report that a majority of individuals with CS have hypo-mineralization of enamel, the outer covering of teeth, and that similar defects are present in a CS mouse model. Comprehensive analysis of the mouse model revealed that ameloblasts, the cells that generate enamel, lacked polarity, and the ameloblast progenitor cells were hyperproliferative. Ras signals through two main effector cascades, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. To determine through which pathway Ras affects enamel formation, inhibitors targeting either PI3K or MEK 1 and 2 (MEK 1/ 2), kinases in the MAPK pathway, were utilized. MEK1/2 inhibition rescued the hypo-mineralized enamel, normalized the ameloblast polarity defect and restored normal progenitor cell proliferation. In contrast, PI3K inhibition only corrected the progenitor cell proliferation phenotype. We demonstrate for the first time the central role of Ras signaling in enamel formation in CS individuals and present the mouse incisor as a model system to dissect the roles of the Ras effector pathways in vivo.

语种英语
WOS记录号WOS:000330841700010
引用统计
被引频次:15[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57388
专题北京大学第三临床医学院_口腔科
作者单位1.Peking Univ, Dept Stomatol, Hosp 3, Beijing, Peoples R China
2.Univ Calif San Francisco, Dept Orofacial Sci, San Francisco, CA 94143 USA
3.Univ Calif San Francisco, Program Craniofacial & Mesenchymal Biol, San Francisco, CA 94143 USA
4.Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA
5.Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
6.Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA
7.Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA
8.Univ Illinois, Coll Dent, Brodie Lab Craniofacial Genet, Chicago, IL USA
9.Univ Toronto, Matrix Dynam Grp, Fac Dent, Toronto, ON M5S 1A1, Canada
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Goodwin, Alice F.,Tidyman, William E.,Jheon, Andrew H.,et al. Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation[J]. HUMAN MOLECULAR GENETICS,2014,23(3):682-692.
APA Goodwin, Alice F..,Tidyman, William E..,Jheon, Andrew H..,Sharir, Amnon.,Zheng, Xu.,...&Klein, Ophir D..(2014).Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation.HUMAN MOLECULAR GENETICS,23(3),682-692.
MLA Goodwin, Alice F.,et al."Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation".HUMAN MOLECULAR GENETICS 23.3(2014):682-692.
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