PUBLICATION
Defining function of wild-type and three patient specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma
- Authors
- Chen, J., Baxi, K., Lipsitt, A.E., Hensch, N.R., Wang, L., Sreenivas, P., Modi, P., Zhao, X.R., Baudin, A., Robledo, D.G., Bandyopadhyay, A., Sugalski, A., Challa, A.K., Kurmashev, D., Gilbert, A.R., Tomlinson, G.E., Houghton, P., Chen, Y., Hayes, M.N., Chen, E.Y., Libich, D.S., Ignatius, M.S.
- ID
- ZDB-PUB-230603-29
- Date
- 2023
- Source
- eLIFE 12: (Journal)
- Registered Authors
- Challa, Anil Kumar, Hayes, Madeline
- Keywords
- cancer biology, zebrafish
- Datasets
- GEO:GSE213869
- MeSH Terms
-
- Animals
- Carcinogenesis
- Cerebellar Neoplasms*
- Mutation
- Proto-Oncogene Proteins p21(ras)/metabolism
- Rhabdomyosarcoma, Embryonal*/metabolism
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37266578 Full text @ Elife
Citation
Chen, J., Baxi, K., Lipsitt, A.E., Hensch, N.R., Wang, L., Sreenivas, P., Modi, P., Zhao, X.R., Baudin, A., Robledo, D.G., Bandyopadhyay, A., Sugalski, A., Challa, A.K., Kurmashev, D., Gilbert, A.R., Tomlinson, G.E., Houghton, P., Chen, Y., Hayes, M.N., Chen, E.Y., Libich, D.S., Ignatius, M.S. (2023) Defining function of wild-type and three patient specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma. eLIFE. 12:.
Abstract
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 TP53P153D and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRASG12D-driven ERMS-model.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping