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: Ji Hae Seo, Jong-Ho Cha, Ji-Hyeon Park, Chul-Ho Jeong, Zee-Yong Park, Hye-Suk Lee, Seung Hyun Oh, Ju-Hee Kang, Se Won Suh, Kyoung Hoon Kim, Jun Yong Ha, Sang Hee Han, Se-Hee Kim, Ji-Won Lee, Jeong Ae Park, Joo-Won Jeong, Kong-Joo Lee, Goo Taeg Oh, Mi-Ni Lee, Sung Won Kwon, Seung-Ki Lee, Kwang-Hoon Chun, Su-Jae Lee, Kyu-Won Kim
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 11 Pg. 4422-32 (Jun 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20501853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AACR.

Chemical References

• CCND1 protein, human
• CTNNB1 protein, human
• Transcription Factor AP-1
• beta Catenin
• Cyclin D1
• Acetyl Coenzyme A
• Acetyltransferases
• N-Terminal Acetyltransferase A
• NAA10 protein, human
• N-Terminal Acetyltransferase E

Topics

• Acetyl Coenzyme A (metabolism)
• Acetylation
• Acetyltransferases (metabolism)
• Animals
• Cell Growth Processes (physiology)
• Cyclin D1 (metabolism)
• HeLa Cells
• Humans
• Mice
• N-Terminal Acetyltransferase A
• N-Terminal Acetyltransferase E
• Neoplasms (enzymology, pathology)
• Transcription Factor AP-1 (metabolism)
• Up-Regulation
• beta Catenin (metabolism)