Tumors derived from ARH1+/- mice and ARH1+/- cells grown in nude mice have mutations in the functional ARH1 allele that affect ARH1 catalytic activity, anti-tumorigenic action, and reversal of toxin-catalyzed ADP-ribosylation

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NHLBI	CANCER-16

Authors

• J. Kato
• D. Vekhter
• J. Heath
• J. Zhu
• M. Mashimo
• J.T. Barbieri
• J. Moss

Abstract

Mono-ADP-ribosylation, a modification in which ADP-ribose from β-NAD is transferred to a protein, is regulated by ADP-ribosyltransferases that ADP-ribosylate proteins and ADP-ribosyl-acceptor hydrolases that cleave the ADP-ribose-acceptor bond. ADP-ribosyl-acceptor hydrolase 1 (ARH1) is responsible for hydrolysis of α-ADP-ribose(arginine)protein. ARH1-/- and ARH1+/- cells produced tumors when injected into nude mice and ARH1-/- and ARH1+/- mice spontaneously developed tumors (Kato et al, 2011 Cancer Res.). We postulated that in heterozygous mice and cells the single functional ARH1 allele had been inactivated, which enabled tumor formation. We found a loss of immunoreactive ARH1 protein in 6 of 16 adenocarcinomas that formed spontaneously in ARH1+/- mice. In the other 25 tumors, where an immunoreactive ARH1 protein band was present, DNA sequencing showed 14 different ARH1 gene mutations in the single ARH1 allele, all located in exon 2 or 3. These mutant genes generated proteins with reduced ARH1 activity. Also, these ARH1 mutants differentially affected intoxication of cells by cholera toxin and Pseudomonas aeruginosa exoenzyme S, bacterial toxins that function through ADP-ribosylation. Thus, control of protein-ADP-ribosylation by ARH1 is important for tumorigenesis and sensitivity to bacterial toxins.

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