title: Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis.
abstract: Human embryonic stem (hES) cells activate a rapid apoptotic response after DNA damage but the underlying mechanisms are unknown. A critical mediator of apoptosis is Bax, which is reported to become active and translocate to the mitochondria only after apoptotic stimuli. Here we show that undifferentiated hES cells constitutively maintain Bax in its active conformation. Surprisingly, active Bax was maintained at the Golgi rather than at the mitochondria, thus allowing hES cells to effectively minimize the risks associated with having preactivated Bax. After DNA damage, active Bax rapidly translocated to the mitochondria by a p53-dependent mechanism. Interestingly, upon differentiation, Bax was no longer active, and cells were not acutely sensitive to DNA damage. Thus, maintenance of Bax in its active form is a unique mechanism that can prime hES cells for rapid death, likely to prevent the propagation of mutations during the early critical stages of embryonic development.
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Raluca
authors.initials: R
authors.lastname: Dumitru
authors.forename: Vivian
authors.initials: V
authors.lastname: Gama
authors.forename: B Matthew
authors.initials: BM
authors.lastname: Fagan
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Bower
authors.forename: Vijay
authors.initials: V
authors.lastname: Swahari
authors.forename: Larysa H
authors.initials: LH
authors.lastname: Pevny
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
mesh_terms: D000107:Acetylation; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis; D001692:Biological Transport; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D020868:Gene Silencing; D019254:Genes, bcl-2; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D008928:Mitochondria / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; C494826:BAX protein, human; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen