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.

The NAD metabolome — a key determinant of cancer cell biology

“…Whether this protein modification has any role in tumour biology is unknown. However, a recent study established that deletion of the Arh1 gene, which encodes an enzyme that reverses monoADP ribosylation of cell surface proteins, increased the incidences of lymphomas, adenocarcinomas and melanomas in mice 39 . Consequently, these observations suggest that deregulation of monoADP ribosylation may affect cancer development or progression.…”

Serum Proteomic Profiling of Lung Adenocarcinoma with Brain Metastasis Based on Matrix-Assisted Laser Ionization Time of Flight Mass Spectrometry Analysis

“…8 and 1984.683 Da achieved a accuracy of 82% with a sensitivity of 84.6% and a specificity of 79.2% to discriminate advanced lung adenocarcinoma with BM from patients without BM. Peptide m/z 1781.8 was identified as a degraded fragment of ADP-ribosylarginine hydrolase (ARH1),which can regulates cell proliferation and tumorigenesis (13). Meanwhile, Peptide 1984.7, a degraded derivative of thymosin beta-4-like protein 3(TMSL3), may be an significant prognostic biomarker for lung adenocarcinoma patients with BM.…”

Inhibition of arginine ADP-ribosyltransferase 1 reduces the expression of poly(ADP-ribose) polymerase-1 in colon carcinoma

“…In a recent study, Kato et al reported that the absence of ADP-ribosylarginine hydrolase (ARH1), arginine-specific mono-ADP-ribosylation hydrolase, may increase the frequency and extent of tumorigenesis in mice, including lung adnocarcinoma, hepatocellular carcinoma and lymphoma (31). They suggested that the levels of protein ADP-ribosylation controlled by ARH1 may suppress carcinoma.…”

“…ARH1, which has an opposite function to ART1, cleaves α-ADP-ribose-arginine to regenerate the arginine-guanidino group (1,32). The knockdown of ARH1 in cells has been shown to increase the ADP-ribose-arginine content (31). Hence, the suppression of carcinogenesis by ARH1 suggests that ART1 has a positive effect on carcinogenesis.…”