TAp73 Knockout Shows Genomic Instability with Infertility and Tumor Suppressor Functions

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2008 Sep 23

PMID 18805989

Citations 265

Authors

Richard Tomasini

Katsuya Tsuchihara

Margareta Wilhelm

Masashi Fujitani

Alessandro Rufini

Carol C Cheung

Fatima Khan

Annick Itie-Youten

Andrew Wakeham

Ming-Sound Tsao

Juan L Iovanna

Jeremy Squire

Igor Jurisica

David Kaplan

Gerry Melino

Andrea Jurisicova

Tak W Mak

Affiliations

Soon will be listed here.

Abstract

The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and DeltaNp73, with opposing pro- and anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles of p73 isoforms in cellular events such as tumor initiation, embryonic development, and cell death remain unclear. To determine which aspects of p73 function are attributable to the TAp73 isoforms, we generated and characterized mice in which exons encoding the TAp73 isoforms were specifically deleted to create a TAp73-deficient (TAp73(-/-)) mouse. Here we show that mice specifically lacking in TAp73 isoforms develop a phenotype intermediate between the phenotypes of Trp73(-/-) and Trp53(-/-) mice with respect to incidence of spontaneous and carcinogen-induced tumors, infertility, and aging, as well as hippocampal dysgenesis. In addition, cells from TAp73(-/-) mice exhibit genomic instability associated with enhanced aneuploidy, which may account for the increased incidence of spontaneous tumors observed in these mutants. Hence, TAp73 isoforms exert tumor-suppressive functions and indicate an emerging role for Trp73 in the maintenance of genomic stability.

Citing Articles

Re-appraising the evidence for the source, regulation and function of p53-family isoforms.

Lopez I, Valdivia I, Vojtesek B, Fahraeus R, Coates P Nucleic Acids Res. 2024; 52(20):12112-12129.

PMID: 39404067 PMC: 11551734. DOI: 10.1093/nar/gkae855.

Mouse cortical organoids reveal key functions of p73 isoforms: TAp73 governs the establishment of the archetypical ventricular-like zones while DNp73 is central in the regulation of neural cell fate.

Alonso-Olivares H, Marques M, Prieto-Colomina A, Lopez-Ferreras L, Martinez-Garcia N, Vazquez-Jimenez A Front Cell Dev Biol. 2024; 12:1464932.

PMID: 39376628 PMC: 11456701. DOI: 10.3389/fcell.2024.1464932.

A novel TAp73-inhibitory compound counteracts stemness features of glioblastoma stem cells.

Villoch-Fernandez J, Martinez-Garcia N, Martin-Lopez M, Maeso-Alonso L, Lopez-Ferreras L, Vazquez-Jimenez A Mol Oncol. 2024; 19(3):852-877.

PMID: 39090849 PMC: 11887682. DOI: 10.1002/1878-0261.13694.

Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73.

Li D, Kok C, Wang C, Ray D, Osterburg S, Dotsch V Proc Natl Acad Sci U S A. 2024; 121(21):e2318591121.

PMID: 38739802 PMC: 11127001. DOI: 10.1073/pnas.2318591121.

RAC1b Collaborates with TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer.

Ungefroren H, Reimann J, Konukiewitz B, Braun R, Wellner U, Lehnert H Biomedicines. 2024; 12(1).

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