title: Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak.
abstract: The pro-apoptotic multidomain Bcl-2 proteins Bax and Bak (also known as BAK1) are considered the gatekeepers of the intrinsic pathway of apoptosis by triggering the mitochondrial release of cytochrome c The role of the third Bax- and Bak-homologous multidomain protein Bok, however, is still unresolved. As cells doubly deficient for Bax and Bak are largely resistant to various apoptotic stimuli, it has been proposed that Bok is either dispensable for apoptosis or that its role is dependent on Bax and Bak. Here, we demonstrate, in several cell systems, that Bok efficiently induces cytochrome c release and apoptosis even in the complete absence of both Bak and Bax. Moreover, modulation of endogenous Bok levels affects the apoptosis response. By RNA interference and targeted deletion of the Bok gene, we demonstrate that Bok can significantly influence the apoptotic response to chemotherapeutic drugs in ovarian carcinoma cells. Hence, our results not only establish Bok as a Bak- and Bax-independent apoptosis inducer, but also suggest a potential impact of Bok expression in ovarian cancer therapy.
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Einsele-Scholz
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Malmsheimer
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Bertram
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stehle
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Johänning
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Manz
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University, Berlin 13125, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University, Berlin 13125, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gillissen
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany frank.essmann@uni-tuebingen.de kso@uni-tuebingen.de.
authors.forename: Klaus
authors.identifier: 0000-0003-1443-2720
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany frank.essmann@uni-tuebingen.de kso@uni-tuebingen.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D054697:Cytostatic Agents / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C503049:BOK protein, human; D054697:Cytostatic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D045304:Cytochromes c
keywords: Apoptosis; Bcl-2-related ovarian killer; Bok; Matador; Ovarian cancer