title: Arrest defective 1 autoacetylation is a critical step in its ability to stimulate cancer cell proliferation.
abstract: The N-acetyltransferase arrest defective 1 (ARD1) is an important regulator of cell growth and differentiation that has emerged recently as a critical molecule in cancer progression. However, the regulation of the enzymatic and biological activities of human ARD1 (hARD1) in cancer is presently poorly understood. Here, we report that hARD1 undergoes autoacetylation and that this modification is essential for its functional activation. Using liquid chromatography-tandem mass spectrometry and site-directed mutational analyses, we identified K136 residue as an autoacetylation target site. K136R mutation abolished the ability of hARD1 to promote cancer cell growth in vitro and tumor xenograft growth in vivo. Mechanistic investigations revealed that hARD1 autoacetylation stimulated cyclin D1 expression through activation of the transcription factors beta-catenin and activator protein-1. Our results show that hARD1 autoacetylation is critical for its activation and its ability to stimulate cancer cell proliferation and tumorigenesis.
authors.affiliation: NeuroVascular Coordination Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Cha
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.forename: Zee-Yong
authors.initials: ZY
authors.lastname: Park
authors.forename: Hye-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Se Won
authors.initials: SW
authors.lastname: Suh
authors.forename: Kyoung Hoon
authors.initials: KH
authors.lastname: Kim
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Ha
authors.forename: Sang Hee
authors.initials: SH
authors.lastname: Han
authors.forename: Se-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Jeong Ae
authors.initials: JA
authors.lastname: Park
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Jeong
authors.forename: Kong-Joo
authors.initials: KJ
authors.lastname: Lee
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Mi-Ni
authors.initials: MN
authors.lastname: Lee
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kwon
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Lee
authors.forename: Kwang-Hoon
authors.initials: KH
authors.lastname: Chun
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D018808:Transcription Factor AP-1; D051176:beta Catenin; D019938:Cyclin D1; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E