title: RGS19 converts iron deprivation stress into a growth-inhibitory signal.
abstract: Iron chelation is a promising therapeutic strategy for cancer that works, in part, by inducing overexpression of N-myc downstream-regulated gene 1 protein (NDRG1), a known growth inhibitor and metastasis suppressor. However, details of the signaling cascades that convert physical stress into a biological response remain elusive. We investigated the role of RGS19, a regulator of G-protein signaling, in iron chelator-induced NDRG1 overexpression in HeLa cells. Knockdown of RGS19 diminished the expression of genes involved in desferrioxamine (DFO)-induced growth inhibition. Conversely, overexpression of RGS19 enhanced the expression of these genes. Moreover, overexpression of RGS19 reduced cell viability. Overexpression of G-protein alpha subunit i3 (Gαi3) repressed the induction of NDRG1 expression. Selective inhibition of downstream targets of Gαi3 abrogated DFO-induced overexpression of NDRG1. DFO protected RGS19 from proteolysis induced by GAIP interacting protein N terminus (GIPN); moreover, an iron-deficient RGS19 mutant was stable in the presence of GIPN and retained GTPase-activating protein activity. RGS19 was co-purified with iron and showed unique UV-absorption characteristics frequently observed in iron-binding proteins. This study demonstrates that RGS19 senses cellular iron availability and is stabilized under iron-depleted conditions, resulting in the induction of a growth-inhibitory signal.
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Junmo
authors.initials: J
authors.lastname: Hwang
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Hyeng-Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Beom Sik
authors.initials: BS
authors.lastname: Kang
authors.affiliation: School of Physics and Energy Science, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Zae Young
authors.initials: ZY
authors.lastname: Ryoo
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Sang-Un
authors.initials: SU
authors.lastname: Choi
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea. Electronic address: slee@knu.ac.kr.
authors.forename: Sanggyu
authors.initials: S
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D003676:Deferoxamine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D007502:Iron Chelating Agents; D020710:RGS Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C492009:GIPC1 protein, human; C097187:regulator of G-protein signalling 19; C498819:GNAI3 protein, human
keywords: Cysteine string motif; Iron-binding protein; N-myc downstream-regulated gene 1 protein; Regulator of G-protein signaling