Novel pathways in Retroviral Tumorigenesis

描述(申请人提供)：一大组逆转录病毒，导致恶性肿瘤，没有认识到癌基因在他们的基因组。这些病毒诱导肿瘤的原因是细胞原癌基因附近的前病毒整合，然后激活其表达。然而，这种情况可能必须重新考虑，因为我们已经发现了一组外源小鼠乳腺肿瘤病毒(MMTV)，它们都具有复制能力，在正常滴度下产生，并可以激活原癌基因的表达，但它们都无法在易感小鼠中诱导乳腺肿瘤。C3 H/HeJ和C3 H/HEN亚株在50多年前从CSH/ST分离出来，CSH/ST是一种感染了MMTV(C3 H)的母株，也是乳腺肿瘤的易患株。我们发现C3H/HeJ小鼠携带的MMTV变异体都是C3H/HEN株仍携带的原始野生型MMTV(C3H)与两个C3H亚株中存在的内源性MTV1之间的重组体。这些重组病毒已经完全失去了在所有C3H小鼠中引起乳腺肿瘤的能力，而野生型MMTV(C3H)在任何一种毒株的小鼠中都具有高度的致瘤性。显然，诱发肿瘤能力的丧失是基于病毒基因组的改变。利用一组嵌合病毒，肿瘤减弱序列已被映射到Gag基因的衣壳(CA)结构域。 重要的是，我们发现与C3H/He小鼠相比，BALB/CJ品系的小鼠对所有MMTV变种引起的乳腺肿瘤高度敏感，这使得能够分析与GAG相互作用的宿主基因。我们已经确定，一个暂时被称为“乳腺肿瘤易感性”或MTS的基因，定位于14号染色体，控制依赖Gag的肿瘤易感性。 我们推测，除了众所周知的MMTV诱导肿瘤发生的机制，即插入突变外，MMTV Gag编码的蛋白还通过与细胞蛋白MTS(直接或间接)合作来增加病毒的致癌潜力，从而直接促进乳腺上皮细胞的转化。这项提案中描述的实验计划将使我们能够确定GAG促进乳腺肿瘤发生的机制。 与公众健康的相关性：拟议的研究将提供有关乳腺肿瘤发生的信号转导途径的基本见解，并最终有助于确定抗肿瘤化疗的潜在靶点。

DESCRIPTION (provided by applicant): A large group of retroviruses, which induce malignancies, do not have appreciated oncogenes in their genomes. Tumor induction by these viruses is explained by proviral integration in the proximity of a cellular proto-oncogene followed by activation of its expression. This scenario, however, may have to be reconsidered, because we have identified a group of exogenous mouse mammary tumor viruses (MMTV) that fail to induce mammary tumors in susceptible mice, even though they are all replication-competent, produced at normal titers and can activate proto-oncogene expression. The C3H/HeJ and C3H/HeN substrains diverged more than 50 years ago from CSH/St, an MMTV (C3H)-infected, and mammary tumor- prone progenitor strains. We found that C3H/HeJ mice carry MMTV variants that are all recombinants between the original wild-type MMTV (C3H), still carried by the C3H/HeN strain, and endogenous Mtv1 present in both C3H substrains. These recombinant viruses have completely lost the ability to cause mammary tumors in all C3H mice, while wild-type MMTV (C3H) is highly tumorigenic in mice from either strain. Clearly, loss of tumor-inducing capacity is based on the alteration of the viral genome. Using a panel of chimeric viruses, the tumor-attenuating sequences have been mapped to the capsid (CA) domain of the gag gene. Importantly, we found that in contrast to C3H/He mice, mice of the BALB/cJ stain are highly susceptible to mammary tumors caused by all MMTV variants, enabling analysis of the host genes involved in interaction with Gag. We have established that a single gene tentatively called "mammary tumor susceptibility" or mts, which maps to Chromosome 14, controls Gag-dependent tumor susceptibility. We hypothesize that in addition to the well-known mechanism of MMTV-induced tumorigenesis, i.e. insertional mutagenesis, MMTV gag-encoded proteins also directly contribute to the transformation of mammary epithelial cells by cooperating with cellular protein Mts (directly or indirectly) to increase the oncogenic potential of the virus. The experimental plan described in this proposal will allow us to determine the mechanism by which Gag contributes to mammary tumorigenesis. Relevance to public health: The proposed studies will provide fundamental insights into signal transduction pathway involved in mammary gland tumorigenesis and ultimately help to identify potential targets for anti-tumor chemotherapy.