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Effects of ADP-ribosylarginine hydrolase (ARH1) on cell proliferation and tumorigenesis

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center




  • J Kato
  • J Zhu
  • C Liu
  • M Stylianou
  • V Hoffmann
  • MJ Lizak
  • CG Glasgow
  • J Moss


Protein mono-ADP-ribosylation, a reversible post-translational modification in which ADP-ribose from NAD is transferred to an amino acid acceptor, is regulated by enzymes that catalyze opposing arms of ADP-ribosylation cycles. ADP-ribosyltransferases 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 α-ADP-ribose-(arginine)protein bond, formed by NAD:arginine ADP-ribosyltransferases. ARH1-/- cells grown from ARH1 knockout mouse embryos had higher proliferation rates and formed more colonies in soft agar than ARH1-/- cells over-expressing the wild-type ARH1 gene (ARH1-/-+wt). Similarly, ARH1-/- cells, but not ARH1-/-+wt cells, produced tumors in nude mice. ARH1+/- cells also produced tumors in nude mice, similar microscopically to those seen with ARH1-/- cells. Consistent with a role for ADP-ribosylation in tumorigenesis and tumor formation, ARH1-/- and ARH1+/- mice spontaneously developed tumors (e.g., lung adenocarcinoma, hepatocellular carcinoma) more frequently than ARH1+/+ mice, as assessed by magnetic resonance imaging (MRI). ARH1 genotype was significantly associated with tumors and metastasis. cDNA and genomic DNA from tumors growing in ARH1+/- mice and from nude mice injected with ARH1+/- cells contained a mutation in the remaining ARH1 allele, or loss of heterozygosity. Thus, post-translational modification of proteins by ADP-ribosylation regulates cell proliferation and tumorigenesis.

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