In:
eLife, eLife Sciences Publications, Ltd, Vol. 12 ( 2023-06-02)
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 kRAS G12D -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 TP53 C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53 P153Δ and TP53 Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53 P153Δ unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRAS G12D -driven ERMS-model.
Type of Medium:
Online Resource
ISSN:
2050-084X
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2023
detail.hit.zdb_id:
2687154-3
