hBub1 negatively regulates p53 mediated early cell death upon mitotic checkpoint activation.
Our previous studies showed that the depletion of the outer kinetochore protein hBub1 upon activation of spindle assembly checkpoint (SAC) primarily triggers early cell death mediated by p53 rather than aneuploidy. Here, we report that phosphorylation of p53 at Ser37 is critical for proapoptotic activity upon SAC activation. Furthermore, we show that p53 physically interacts with hBub1 at kinetochores in response to mitotic spindle damage suggesting a direct role for hBub1 in the suppression of p53 mediated cell death. This observation is further substantiated by the inhibition of p53 mediated transactivation of the proapoptotic target genes, PUMA and BAX, by hBub1 in SAC activated cells. In summary, our data from these and our previous studies strongly suggest that in response to SAC activation, hBub1 acts as a negative regulator of p53 mediated early cell death in a novel checkpoint pathway. On the translational medicine front, it is tempting to speculate that by disabling hBub1 in p53 proficient cancer cells, apoptosis may be induced as a therapeutic approach to eradicate the tumor cells.
Gao
Fangming
F
Department of Medicine, Genetics Program and Cancer Research Center, Boston University School of Medicine, Boston, MA, USA.
Ponte
Jose F
JF
Levy
Mary
M
Papageorgis
Panagiotis
P
Cook
Nathaniel M
NM
Ozturk
Sait
S
Lambert
Arthur W
AW
Thiagalingam
Arunthathi
A
Abdolmaleky
Hamid M
HM
Sullivan
Beth A
BA
Thiagalingam
Sam
S
D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole