TAp73 knockout shows genomic instability with infertility and tumor suppressor functions.
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.
Tomasini
Richard
R
The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario M5G 2C1, Canada.
Tsuchihara
Katsuya
K
Wilhelm
Margareta
M
Fujitani
Masashi
M
Rufini
Alessandro
A
Cheung
Carol C
CC
Khan
Fatima
F
Itie-Youten
Annick
A
Wakeham
Andrew
A
Tsao
Ming-Sound
MS
Iovanna
Juan L
JL
Squire
Jeremy
J
Jurisica
Igor
I
Kaplan
David
D
Melino
Gerry
G
Jurisicova
Andrea
A
Mak
Tak W
TW
D000375:Aging / Q000235:genetics / Q000502:physiology; D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D005260:Female; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability; D006624:Hippocampus / Q000002:abnormalities; D007247:Infertility, Female / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011247:Pregnancy; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C454920:delta Np73, mouse