Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma

doi:10.7554/eLife.68221

科研成果详情

题名	Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma
作者	Chen, Jiangfei1,2; Baxi, Kunal 2,3; Lipsitt, Amanda E.2,4; Hensch, Nicole Rae 2,3; Wang, Long 2,3; Sreenivas, Prethish 2,3; Modi, Paulomi 2,3; Zhao, Xiang Ru 2,3; Baudin, Antoine 2,5; Robledo, Daniel G.2; Bandyopadhyay, Abhik 2; Sugalski, Aaron 4; Challa, Anil K.2,6; Kurmashev, Dias 2; Gilbert, Andrea R.7; Tomlinson, Gail E.2,4; Houghton, Peter 2,3; Chen, Yidong 8; Hayes, Madeline N.9; Chen, Eleanor Y.10; Libich, David S.2,5; Ignatius, Myron S.2,3
发表日期	2023-06-02
发表期刊	eLife 影响因子和分区
语种	英语
原始文献类型	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
关键词	TP53 TP53C176F TP53P153Δ TP53Y220C cancer biology mutant tp53 rare varients rhabdomyosarcoma tumor initiation zebrafish
其他关键词	SELF-RENEWAL ; MUTANT P53 ; REGULATES GROWTH ; CANCER ; PATHWAY ; EXPRESSION ; LANDSCAPE ; FREQUENCY ; PROTEIN ; CELLS
摘要	In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153Δ and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153Δ unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRASG12D-driven ERMS-model
资助项目	NIH HHS[R00CA1715184];NIH HHS[S10 OD030311];NCATS NIH HHS[TL1 TR002647];NCI NIH HHS[T32 CA148724];NCI NIH HHS[P30 CA054174];NIH HHS[R00CA175184];NCI NIH HHS[R00 CA175184]
出版者	eLIFE SCIENCES PUBL LTD
ISSN	2050-084X
卷号	12
DOI	10.7554/eLife.68221
页数	27
WOS类目	Biology
WOS研究方向	Life Sciences & Biomedicine - Other Topics
WOS记录号	WOS:001071875400001
收录类别	PUBMED ; SCIE ; SCOPUS
URL	查看原文
PubMed ID	37266578
SCOPUSEID	2-s2.0-85164239629
自科自定义期刊分类	T3(B)类
通讯作者地址	[Ignatius, Myron S.]Greehey Children's Cancer Research Institute (GCCRI),UT Health Sciences Center,San Antonio,United States
Scopus学科分类	Neuroscience (all);Biochemistry, Genetics and Molecular Biology (all);Immunology and Microbiology (all)
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/181152
专题	公共卫生学院_环境安全与健康风险评估研究院
通讯作者	Ignatius, Myron S.
作者单位	1.Institute of Environmental Safety and Human Health,Wenzhou Medical University,Wenzhou,China; 2.Greehey Children's Cancer Research Institute (GCCRI),UT Health Sciences Center,San Antonio,United States; 3.Department of Molecular Medicine,UT Health Sciences Center,San Antonio,United States; 4.Department of Pediatrics,Division of Hematology Oncology,UT Health Sciences Center,San Antonio,United States; 5.Department of Biochemistry and Structural Biology,UT Health Sciences Center,San Antonio,United States; 6.Department of Biology,University of Alabama at Birmingham,Birmingham,United States; 7.Department of Pathology and Laboratory Medicine,UT Health Sciences Center,San Antonio,United States; 8.Department of Population Health Sciences,UT Health Sciences Center,San Antonio,United States; 9.Developmental and Stem Cell Biology,Hospital for Sick Children,Toronto,Canada; 10.Department of Laboratory Medicine and Pathology,University of Washington,Seattle,United States
第一作者单位	公共卫生学院_环境安全与健康风险评估研究院
第一作者的第一单位	公共卫生学院_环境安全与健康风险评估研究院
推荐引用方式 GB/T 7714	Chen, Jiangfei,Baxi, Kunal,Lipsitt, Amanda E.,et al. Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma[J]. eLife,2023,12.
APA	Chen, Jiangfei., Baxi, Kunal., Lipsitt, Amanda E.., Hensch, Nicole Rae., Wang, Long., ... & Ignatius, Myron S.. (2023). Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma. eLife, 12.
MLA	Chen, Jiangfei,et al."Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma".eLife 12(2023).