title: Pro- and anti-apoptotic dual functions of the C5a receptor: involvement of regulator of G protein signaling 3 and extracellular signal-regulated kinase.
abstract: When apoptosis is initiated by manganese (II) loading, hyperthermia or thapsigargin treatment, human HL-60 and AsPC-1 cells initiate de novo synthesis of the C5a receptor (C5aR) and generation of its ligand, the ribosomal protein S19 (RP S19) homodimer. The ligand-receptor interaction, in an autocrine/paracrine fashion, promotes apoptosis, which can be bypassed by exogenous administration of C5a, another ligand. The proapoptotic function of the RP S19 dimer is reproduced by a C5a/RPS19 chimera that contains the body of C5a and the C-terminal region (Ile134-His145) of RP S19. The RP S19 dimer or C5a/RPS19 and C5a inversely regulate the expression of Regulator of G protein Signaling 3 (RGS3) gene in the apoptosis-initiated cells. Namely, the RP S19-type proteins upregulate RGS3 expression, whereas the C5a reduce it. Transformation of HL-60 cells to overexpress RGS3 promotes apoptosis in association with the downregulation of the Extracellular signal-Regulated Kinase (ERK) signal, and vice versa in the RGS3 knocked-down cells. Consistent with this result, an inhibitor of ERK phosphorylation effectively enhances the apoptotic rate in wild-type HL-60 cells. Moreover, a dominant negative effect on the RP S19 dimer production encourages apoptosis-initiated HL-60 cells with a longer lifespan in mouse than the natural effect. Our data indicate that, in apoptosis-initiated cells, the ligand-dependent C5aR-mediated dual signal affects the fate of cells, either apoptosis execution or survival, through regulation of RGS3 gene expression and subsequent modulation of ERK signal.
authors.affiliation: Department of Molecular Pathology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. seino@kumamoto-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishiura
authors.forename: Hideo
authors.initials: H
authors.lastname: Nonaka
authors.forename: Ivette S
authors.initials: IS
authors.lastname: Revollo
authors.forename: Umeko
authors.initials: U
authors.lastname: Semba
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ota
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Kumiko
authors.initials: K
authors.lastname: Harada
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yamamoto