title: Autoacetylation regulates differentially the roles of ARD1 variants in tumorigenesis.
abstract: ARD1 is an acetyltransferase with several variants derived from alternative splicing. Among ARD1 variants, mouse ARD1(225) (mARD1(225)), mouse ARD1(235) (mARD1(235)), and human ARD1(235) (hARD1(235)) have been the most extensively characterized and are known to have different biological functions. In the present study, we demonstrated that mARD1(225), mARD1(235), and hARD1(235) have conserved autoacetylation activities, and that they selectively regulate distinct roles of ARD1 variants in tumorigenesis. Using purified recombinants for ARD1 variants, we found that mARD1(225), mARD1(235), and hARD1(235) undergo similar autoacetylation with the target site conserved at the Lys136 residue. Moreover, functional investigations revealed that the role of mARD1(225) autoacetylation is completely distinguishable from that of mARD1(235) and hARD1(235). Under hypoxic conditions, mARD1(225) autoacetylation inhibited tumor angiogenesis by decreasing the stability of hypoxia-inducible factor-1α (HIF-1α). Autoacetylation stimulated the catalytic activity of mARD1(225) to acetylate Lys532 of the oxygen-dependent degradation (ODD) domain of HIF-1α, leading to the proteosomal degradation of HIF-1α. In contrast, autoacetylation of mARD1(235) and hARD1(235) contributed to cellular growth under normoxic conditions by increasing the expression of cyclin D1. Taken together, these data suggest that autoacetylation of ARD1 variants differentially regulates angiogenesis and cell proliferation in an isoform-specific manner.
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Tam Thuy Lu
authors.initials: TT
authors.lastname: Vo
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Choi
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Jang
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Wee
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Bum Ju
authors.initials: BJ
authors.lastname: Ahn
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Cha
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Min Wook
authors.initials: MW
authors.lastname: Shin
authors.affiliation: SNU-Harvard Neurovascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D025461:Feedback, Physiological; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008969:Molecular Sequence Data; D063209:N-Terminal Acetyltransferase A / Q000235:genetics* / Q000378:metabolism*; D063213:N-Terminal Acetyltransferase E / Q000235:genetics* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D055550:Protein Stability
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E