Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.
Vault poly(ADP-ribose) polymerase (VPARP) and telomerase-associated protein 1 (TEP1) are components of the vault ribonucleoprotein complex. Vaults have been implicated in multidrug resistance of human tumors and are thought to be involved in macromolecular assembly and/or transport. Previous studies showed that VPARP-deficient mice were viable, fertile, and did not display any vault-related or telomerase-related phenotype, whereas disruption of telomerase-associated protein 1 in mice led to reduced stability of the vault RNA and affected its stable association with vaults, although there were no telomerase-related changes. In this study, we evaluated the susceptibility of Vparp-/- and Tep1-/- mice to dimethylhydrazine-induced colon tumorigenesis and urethane-induced lung tumorigenesis. Mice received i.p. injections of either 1 g/kg body weight of urethane twice a week for 2 weeks or 20 mg/kg body weight of dimethylhydrazine once a week for 10 weeks and were analyzed after 10 and 60 weeks, respectively. The colon tumor incidence and multiplicity were significantly higher and colon tumor latency was significantly shorter in Vparp-/- mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1-/- mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparp-/- and Tep1-/- mice but were not significant. The increase in carcinogen-induced tumors in VPARP-deficient mice is the only phenotype observed to date, and suggests a possible role for VPARP, directly or indirectly, in chemically induced neoplasia.
Raval-Fernandes
Sujna
S
Department of Biological Chemistry and the Jonsson Comprehensive Cancer Center, The David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1737, USA.
Kickhoefer
Valerie A
VA
Kitchen
Christina
C
Rome
Leonard H
LH
D000818:Animals; D002273:Carcinogens; D002352:Carrier Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology*; D004127:Dimethylhydrazines; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics; D016601:RNA-Binding Proteins; D014520:Urethane; D020394:Vault Ribonucleoprotein Particles / Q000172:deficiency* / Q000235:genetics
D002273:Carcinogens; D002352:Carrier Proteins; D004127:Dimethylhydrazines; D016601:RNA-Binding Proteins; C498415:Tep1 protein, mouse; D020394:Vault Ribonucleoprotein Particles; D014520:Urethane; D011065:Poly(ADP-ribose) Polymerases; C449359:vault poly(ADP-ribose) polymerase