ADP-Ribosylarginine Hydrolase Regulates Cell Proliferation and Tumorigenesis

作者：Jiro Kato, Jianfeng Zhu, Chengyu Liu, Mario Stylianou, Victoria Hoffmann, Martin J. Lizak, Connie G. Glasgow, Joel Moss · 发表于：Cancer Research · 年份：2011 · DOI：10.1158/0008-5472.can-10-0733 · 被引用次数：47 · 研究领域：PARP inhibition in cancer therapy、Toxin Mechanisms and Immunotoxins、Calcium signaling and nucleotide metabolism

Protein ADP-ribosylation is a reversible posttranslational modification of uncertain significance in cancer. In this study, we evaluated the consequences for cancer susceptibility in the mouse of a genetic deletion of the enzyme responsible for removing mono-ADP-ribose moieties from arginines in cellular proteins. Specifically, we analyzed cancer susceptibility in animals lacking the ADP-ribosylarginine hydrolase (ARH1) that cleaves the ADP ribose-protein bond. ARH1(-/-) cells or ARH1(-/-) cells overexpressing an inactive mutant ARH1 protein (ARH1(-/-)+dm) had higher proliferation rates than either wild-type ARH1(+/+) cells or ARH1(-/-) cells engineered to express the wild-type ARH1 enzyme. More significantly, ARH1(-/-) and ARH1(+/-) mice spontaneously developed lymphomas, adenocarcinomas, and metastases more frequently than wild-type ARH1(+/+) mice. In ARH1(+/-) mice, we documented in all arising tumors mutation of the remaining wild-type allele (or loss of heterozygosity), illustrating the strict correlation that existed between tumor formation and absence of ARH1 gene function. Our findings show that proper control of protein ADP-ribosylation levels affected by ARH1 is essential for cancer suppression.