Increased Susceptibility of Vault Poly(ADP-Ribose) Polymerase–Deficient Mice to Carcinogen-Induced Tumorigenesis

Abstract

Vault poly(ADP-ribose) polymerase (VPARP) and telomeraseassociated 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 À/À and Tep1mice 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 À/À mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1 À/À mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparpand Tep1 À/À 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.

Vaults and the major vault protein: Novel roles in signal pathway regulation and immunity

“…In contrast to PARP1, however, vPARP does not seem to be activated by DNA damage [5] and vPARP (-/-) mice have no obvious chromosomal instability phenotype [77]. Interestingly, vPARP (-/-) mice are hypersensitive to dimethylhydrazine-induced colon cancer and to a lesser extent urethane-induced lung carcinogenesis [78]. These data suggest that vPARP or vaults are involved in the repair of DNA damage caused, for example, by alkylating agents.…”

A Relational Learning Approach to Structure-Activity Relationships in Drug Design Toxicity Studies

“…Methyhydrazines are associated with a number of diseases, particularly cancer [40,41,42]. The same applies to nitroso(propyl)amines and nitrosamines in general, which strongly interact with the CYP2A6 cytochrome causing hepatitis B and C, liver cancer and cirrhosis, and several other types of cancer [43,44,45].…”

Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability

“…PARP1 and PARP2 possess both overlapping and nonredundant functions in the maintenance of genomic stability [27]. In addition, increased susceptibility to carcinogen-induced colon cancer development was observed in PARP4-deficient mice [28]. Despite such importance in carcinogenesis, alterations of PARP genes in human cancers are largely unknown.…”

“…PARP9, PARP14, and PARP15, in common, have macro domains that are supposed to function as an ADP-ribose phosphoesterase that might regulate protein(ADP-ribosyl)ation [1]. PARP14 is known to have transcriptional regulation activity in response to cytokine [28] and to exhibit PARP activity [29]. Selective expression of PARP14 in intestinal epithelial cells as well as in lymphoid cells suggests that it might have a role in the gastrointestinal tract [28].…”

“…PARP14 is known to have transcriptional regulation activity in response to cytokine [28] and to exhibit PARP activity [29]. Selective expression of PARP14 in intestinal epithelial cells as well as in lymphoid cells suggests that it might have a role in the gastrointestinal tract [28]. The PARP14 mutations (p. Asn1322IlefsX26 and p.Asn1322Leufsx20) are predicted to save the macro domains (within amino acids 641-1164) but to remove the PARP catalytic domain (1513-1636) [29].…”