Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.
Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.
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DOI：
10.1158/0008-5472.can-05-0770
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发表时间：
2005-10
期刊：
影响因子：
11.2
通讯作者：
S. Raval‐Fernandes;V. Kickhoefer;C. Kitchen;L. Rome
中科院分区：
文献类型：
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作者：
S. Raval‐Fernandes;V. Kickhoefer;C. Kitchen;L. Rome
穹窿体多聚（ADP-核糖）聚合酶（VPARP）和端粒酶相关蛋白1（TEP 1）是穹窿体核糖核蛋白复合物的组成部分。穹窿与人类肿瘤的多药耐药性有关，并被认为参与大分子的组装和/或转运。先前的研究表明，VPARP缺陷小鼠是可行的，可生育的，并没有表现出任何穹窿相关或端粒酶相关的表型，而在小鼠中破坏端粒酶相关蛋白1导致穹窿RNA的稳定性降低，并影响其与穹窿的稳定关联，尽管没有端粒酶相关的变化。在这项研究中，我们评估了Vparp-/-和Tep 1-/-小鼠对二甲基肼诱导的结肠肿瘤发生和二甲基肼诱导的肺肿瘤发生的易感性。小鼠每周两次接受1 g/kg体重的尿烷腹腔注射，持续2周，或每周一次接受20 mg/kg体重的二甲基肼腹腔注射，持续10周，并分别在10周和60周后进行分析。与野生型小鼠相比，Vparp-/-小鼠的结肠肿瘤发生率和多样性显著更高，结肠肿瘤潜伏期显著更短。在Tep 1-/-小鼠中也观察到结肠肿瘤发生率增加、多重性增加和肿瘤潜伏期减少，然而，这些结果在统计学上不显著。Vparp-/-和Tep 1-/-小鼠的肺肿瘤多样性均增加，但不显著。VPARP缺陷小鼠中致癌物诱导的肿瘤增加是迄今为止观察到的唯一表型，表明VPARP可能直接或间接地在化学诱导的肿瘤形成中发挥作用。
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.