title: TAp73 knockout shows genomic instability with infertility and tumor suppressor functions.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Tomasini
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
authors.forename: Margareta
authors.initials: M
authors.lastname: Wilhelm
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujitani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rufini
authors.forename: Carol C
authors.initials: CC
authors.lastname: Cheung
authors.forename: Fatima
authors.initials: F
authors.lastname: Khan
authors.forename: Annick
authors.initials: A
authors.lastname: Itie-Youten
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: David
authors.initials: D
authors.lastname: Kaplan
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: 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
chemical_list: D017931:DNA Primers; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C454920:delta Np73, mouse