title: hBub1 deficiency triggers a novel p53 mediated early apoptotic checkpoint pathway in mitotic spindle damaged cells.
abstract: It has been universally believed that spindle assembly checkpoint (SAC) proteins which include the kinetochore proteins are involved in monitoring the faithful segregation of sister chromatids during cell division and hence defects in these proteins result in aneuploidy. Furthermore, there are multiple sources of experimental data to suggest that a defect in p53 can also promote genomic instability leading to aneuploidy. Despite these observations, a molecular basis for the prevention of aneuploidy to maintain genomic integrity upon activation of SAC has largely remained elusive. In this report, we demonstrate a novel mechanism for the maintenance of a balance between cell survival and apoptosis upon activation of SAC. We found that depletion of the outer kinetochore protein hBub1 upon activation of SAC primarily triggers early cell death mediated by p53. This phenomenon is further supported by the upregulation of p53 downstream pro-apoptotic genes, BAX and PUMA as well as a corresponding increase in the cleavage products of PARP and caspase 3, markers of apoptosis, upon depletion of hBub1 in SAC activated cells. On the other hand, as expected, concomitant loss of both hBub1 and p53 resulted in disabling of the p53 mediated cell death pathway leading to the accumulation of cells with aneuploidy/polyploidy.
authors.affiliation: Department of Medicine, Genetics Program and Cancer Research Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Fangming
authors.initials: F
authors.lastname: Gao
authors.forename: Jose F
authors.initials: JF
authors.lastname: Ponte
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.forename: Mary
authors.initials: M
authors.lastname: Levy
authors.forename: Sait
authors.initials: S
authors.lastname: Ozturk
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Lambert
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Dharmaraj
authors.initials: D
authors.lastname: Chinnappan
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
authors.forename: Arunthathi
authors.initials: A
authors.lastname: Thiagalingam
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Abdolmaleky
authors.forename: Sam
authors.initials: S
authors.lastname: Thiagalingam
mesh_terms: D000782:Aneuploidy; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D064246:Mad2 Proteins; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases