title: ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway.
abstract: The apoptosis-associated speck-like protein (ASC) is an unusual adaptor protein that contains the Pyrin/PAAD death domain in addition to the CARD protein-protein interaction domain. Here, we present evidence that ASC can function as an adaptor molecule for Bax and regulate a p53-Bax mitochondrial pathway of apoptosis. When ectopically expressed, ASC interacted directly with Bax, colocalized with Bax to the mitochondria, induced cytochrome c release with a significant reduction of mitochondrial membrane potential and resulted in the activation of caspase-9, -2 and -3. The rapid induction of apoptosis by ASC was not observed in Bax-deficient cells. We also show that induction of ASC after exposure to genotoxic stress is dependent on p53. Blocking of endogenous ASC expression by small-interfering RNA (siRNA) reduced the apoptotic response and inhibited translocation of Bax to mitochondria in response to p53 or genotoxic insult, suggesting that ASC is required to translocate Bax to the mitochondria. Our findings demonstrate that ASC has an essential role in the intrinsic mitochondrial pathway of apoptosis through a p53-Bax network.
authors.affiliation: Cancer Biology Program, Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Yohji A
authors.initials: YA
authors.lastname: Minamishima
authors.forename: Salvador
authors.initials: S
authors.lastname: Macip
authors.forename: Junji
authors.initials: J
authors.lastname: Sagara
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C402202:PYCARD protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases