ADP-ribosylarginine hydrolase regulates cell proliferation and tumorigenesis.

Abstract

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.

• Authors: Jiro Kato, Jianfeng Zhu, Chengyu Liu, Mario Stylianou, Victoria Hoffmann, Martin J Lizak, Connie G Glasgow, Joel Moss
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 15 Pg. 5327-35 (Aug 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21697277 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Neoplasm Proteins
• Adenosine Diphosphate Ribose
• ADP-ribosylarginine
• N-Glycosyl Hydrolases
• ADP-ribosylarginine hydrolase

Topics

• Adenosine Diphosphate Ribose (analogs & derivatives, metabolism)
• Animals
• Cell Division
• Cell Transformation, Neoplastic (genetics, metabolism)
• Female
• Genetic Predisposition to Disease
• Genotype
• Loss of Heterozygosity
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• N-Glycosyl Hydrolases (deficiency, genetics, physiology)
• Neoplasm Metastasis (genetics)
• Neoplasm Proteins (physiology)
• Neoplasms, Experimental (enzymology, genetics)
• Protein Processing, Post-Translational
• Tumor Stem Cell Assay