Arrest defective 1 autoacetylation is a critical step in its ability to stimulate cancer cell proliferation.
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.
Seo
Ji Hae
JH
NeuroVascular Coordination Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Cha
Jong-Ho
JH
Park
Ji-Hyeon
JH
Jeong
Chul-Ho
CH
Park
Zee-Yong
ZY
Lee
Hye-Suk
HS
Oh
Seung Hyun
SH
Kang
Ju-Hee
JH
Suh
Se Won
SW
Kim
Kyoung Hoon
KH
Ha
Jun Yong
JY
Han
Sang Hee
SH
Kim
Se-Hee
SH
Lee
Ji-Won
JW
Park
Jeong Ae
JA
Jeong
Joo-Won
JW
Lee
Kong-Joo
KJ
Oh
Goo Taeg
GT
Lee
Mi-Ni
MN
Kwon
Sung Won
SW
Lee
Seung-Ki
SK
Chun
Kwang-Hoon
KH
Lee
Su-Jae
SJ
Kim
Kyu-Won
KW
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
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