title: The Adhesion GPCR CD97/ADGRE5 inhibits apoptosis.
abstract: The Adhesion G protein-coupled receptor (GPCR) CD97/ADGRE5 is induced, upregulated, and/or biochemically modified in various malignancies, compared to the corresponding normal tissues. As tumor cells are generally more resistant to apoptosis, we here studied the ability of CD97 to regulate tumor cell survival under apoptotic conditions. Stable overexpression of wild-type CD97 reduced serum starvation- and staurosporine-induced intrinsic and tumor necrosis factor (TNF)/cycloheximide-induced extrinsic apoptosis, indicated by an increase in cell viability, a lower percentage of cells within the subG0/G1 phase, expressing annexin V, or having condensed nuclei, and a reduction of DNA laddering. Protection from cell death by CD97 was accompanied by an inhibition of caspase activation and modulation of anti- and pro-apoptotic members of the BCL-2 superfamily. shRNA-mediated knockdown of CD97 and, in part, truncation of the seven-span transmembrane (TM7) region of CD97 increased caspase-mediated apoptosis. Protection from apoptosis required not only the TM7 region but also cleavage of the receptor at its GPCR proteolysis site (GPS), whereas alternative splicing of its extracellular domain had no effect. Together, our data indicate a role of CD97 in tumor cell survival.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Cheng-Chih
authors.initials: CC
authors.lastname: Hsiao
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Keysselt
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Sittig
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hamann
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan. Electronic address: hhlin@mail.cgu.edu.tw.
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany. Electronic address: gabriela.aust@medizin.uni-leipzig.de.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Aust
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: C095004:ADGRE5 protein, human; D015703:Antigens, CD; D043562:Receptors, G-Protein-Coupled
keywords: Adhesion GPCR; Apoptosis; CD97