北京大学医学部机构知识库
Advanced  
IR@PKUHSC  > 北京大学第三临床医学院  > 口腔科  > 期刊论文
学科主题: 口腔医学
题名:
Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation
作者: 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
发表日期: 2014-02-01
DOI: 10.1093/hmg/ddt455
卷: 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
所属项目编号: F30-DE022205 ; K99-DE022059 ; R01-AR062165 ; R01-DE021420 ; DP2-OD00719 ; MOP-119310 ; RGPIN-403292-11
项目资助者: National Institutes of Health ; Canadian Institutes of Health Research ; Natural Sciences and Engineering Research Council of Canada
WOS记录号: WOS:000330841700010
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/57388
Appears in Collections:北京大学第三临床医学院_口腔科_期刊论文

Files in This Item:

There are no files associated with this item.


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

Recommended Citation:
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.
Service
Recommend this item
Sava as my favorate item
Show this item's statistics
Export Endnote File
Google Scholar
Similar articles in Google Scholar
[Goodwin, Alice F.]'s Articles
[Tidyman, William E.]'s Articles
[Jheon, Andrew H.]'s Articles
CSDL cross search
Similar articles in CSDL Cross Search
[Goodwin, Alice F.]‘s Articles
[Tidyman, William E.]‘s Articles
[Jheon, Andrew H.]‘s Articles
Related Copyright Policies
Null
Social Bookmarking
Add to CiteULike Add to Connotea Add to Del.icio.us Add to Digg Add to Reddit

Items in IR are protected by copyright, with all rights reserved, unless otherwise indicated.

 

 

Valid XHTML 1.0!
Copyright © 2007-2017  北京大学医学部 - Feedback
Powered by CSpace