title: 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.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kato
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhu
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Mario
authors.initials: M
authors.lastname: Stylianou
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffmann
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lizak
authors.forename: Connie G
authors.initials: CG
authors.lastname: Glasgow
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D019656:Loss of Heterozygosity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009699:N-Glycosyl Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000502:physiology*; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics; D011499:Protein Processing, Post-Translational; D014410:Tumor Stem Cell Assay
chemical_list: D009363:Neoplasm Proteins; D000246:Adenosine Diphosphate Ribose; C043357:ADP-ribosylarginine; D009699:N-Glycosyl Hydrolases; C046422:ADP-ribosylarginine hydrolase