| Signaling |
| Sig-SIG -12 |
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J. Kato, J. Zhu, A. Kasamatsu, C. Liu, V. Hoffmann, M. Lizak, J. Moss |
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Effects of ADP-ribosylarginine Hydrolase (ARH1) on Cell Proliferation and Tumorigenesis |
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Mono-ADP-ribosylation, a post-translational modification involving the transfer of ADP-ribose from NAD to an acceptor, is regulated by enzymes that catalyze opposing arms of ADP-ribosylation cycles. ADP-ribosyltransferases (ARTs) catalyze the modification of ADP-ribose acceptors, whereas ADP-ribosyl-acceptor hydrolases (ARHs) cleave the ADP-ribose-acceptor bond. ARH1 is responsible for the hydrolysis of the alpha-ADP-ribose-(arginine)protein bond formed by NAD:arginine ADP-ribosyltransferases. ARH1-/- cells from embryonic tissues of an ARH1 knockout mouse, and ARH1-/- cells transformed with an inactive, double-mutant ARH1 gene (ARH1-/-+dm) had a higher proliferation rate than wild-type ARH1+/+ cells and ARH1-/- cells expressing the wild-type ARH1 gene (ARH1-/-+wt). Like ARH1-/- cells, ARH1-/-+dm cells formed more colonies in soft agar than did ARH1+/+ cells or ARH1-/-+wt cells. Similarly, ARH1-/- and ARH1-/-+dm cells, but not ARH1+/+ and ARH1-/-+wt cells, produced tumors in nude mice. ARH1-/- mice also spontaneously developed tumors, e.g., lymphosarcoma, adenocarcinoma, mammary carcinoma, hepatocellular carcinoma, hemangiosarcoma, rhabdomyosarcoma, more frequently than did their wild-type counterparts. As expected based on the proposed function for ARH1 in an ADP-ribosylation cycle(s), basal ADP-ribose-arginine content of ARH1-/- cells and ARH1-/- mouse tissues was higher than those of wild-type cells and tissues. Thus, mono-ADP-ribosylation of arginine residues in proteins appears to have a role in tumorgenesis. |
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