TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity.
The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.
Tomasini
Richard
R
The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario, Canada M5G 2C1.
Tsuchihara
Katsuya
K
Tsuda
Chiharu
C
Lau
Suzanne K
SK
Wilhelm
Margareta
M
Rufini
Alessandro
A
Tsao
Ming-sound
MS
Iovanna
Juan L
JL
Jurisicova
Andrea
A
Melino
Gerry
G
Mak
Tak W
TW
D000818:Animals; D018797:Cell Cycle Proteins; D043171:Chromosomal Instability; D005260:Female; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology*; D008941:Spindle Apparatus / Q000737:chemistry / Q000502:physiology*
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C454920:delta Np73, mouse; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases