title: Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization.
abstract: PCAF and ADA3 associate within the same macromolecular complexes to control the transcription of many genes, including some that regulate apoptosis. Here we show that PCAF and ADA3 regulate the expression of PACS1, whose protein product is a key component of the machinery that sorts proteins among the trans-Golgi network and the endosomal compartment. We describe a novel role for PACS1 as a regulator of the intrinsic pathway of apoptosis and mitochondrial outer membrane permeabilization. Cells with decreased PACS1 expression were refractory to cell death mediated by a variety of stimuli that operate through the mitochondrial pathway, including human granzyme B, staurosporine, ultraviolet radiation and etoposide, but remained sensitive to TRAIL receptor ligation. The mitochondria of protected cells failed to release cytochrome c as a result of perturbed oligomerization of BAX and BAK. We conclude that PCAF and ADA3 transcriptionally regulate PACS1 and that PACS1 is a key regulator of BAX/BAK oligomerization and the intrinsic (mitochondrial) pathway to apoptosis.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3052, Australia.|School of Clinical Sciences, Monash University, Clayton 3168, Australia.
authors.forename: Daniella
authors.initials: D
authors.lastname: Brasacchio
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
authors.forename: Amber E
authors.initials: AE
authors.lastname: Alsop
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3052, Australia.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Noori
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
authors.forename: Mariam
authors.initials: M
authors.lastname: Lufti
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
authors.forename: Sweta
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3052, Australia.|Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
authors.forename: Kaylene J
authors.initials: KJ
authors.lastname: Simpson
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton 3168, Australia.
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Bird
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Kluck
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.|Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville 3052, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D044127:Epigenesis, Genetic; D053804:Granzymes; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D055503:Protein Multimerization; D015398:Signal Transduction; D019311:Staurosporine; D014157:Transcription Factors / Q000378:metabolism*; D014466:Ultraviolet Rays; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D053804:Granzymes; D019311:Staurosporine; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494772:BAK1 protein, human; C494826:BAX protein, human; C491914:PACS1 protein, human; C444103:TADA3 protein, human; C509213:GZMB protein, human