Novel pathways in Retroviral Tumorigenesis

逆转录病毒肿瘤发生的新途径

• 批准号: 7264672
• 负责人: Tatyana V Golovkina
• 金额: $ 26.46万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-21 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264672
• 关键词: Attenuated; BALB/cJ Mouse; Biochemical Genetics; C3H/HeJ Mouse; C3H/HeN Mouse; Candidate Disease Gene; Capsid; Cell Nucleus; Cell membrane; Cells; Chromosomes, Human, Pair 14; DNA; Development; Dominant Genes; Epithelial Cells; Gagging; Genes; Genome; Goals; Inbred C3H Mice; Insertional Mutagenesis; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Maps; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplastic Cell Transformation; Nuclear Export; Oncogenes; Oncogenic; Oncogenic Viruses; Pathway interactions; Positioning Attribute; Predisposition; Proteins; Proto-Oncogenes; Public Health; Recombinants; Research Personnel; Resistance; Retroviridae; Signal Transduction Pathway; Staining method; Stains; Transgenic Mice; Transgenic Organisms; Variant; Viral Genome; Virion; Virus; Virus Activation; Virus Replication; base; chemotherapy; insight; mammary tumor virus; membrane assembly; novel; progenitor; programs; recombinant virus; tumor; tumorigenesis; tumorigenic; viral RNA; yeast two hybrid system

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.

描述（由申请方提供）：大量逆转录病毒可诱导恶性肿瘤，但其基因组中不含可识别的致癌基因。这些病毒的肿瘤诱导是通过前病毒整合在细胞原癌基因附近，然后激活其表达来解释的。然而，这种情况可能必须重新考虑，因为我们已经确定了一组外源性小鼠乳腺肿瘤病毒（MMTV），未能在易感小鼠中诱导乳腺肿瘤，即使它们都具有复制能力，以正常滴度产生，并能激活原癌基因表达。C3 H/HeJ和C3 H/HeN亚株在50多年前从CSH/St（MMTV（C3 H）感染的和乳腺肿瘤倾向的祖株）分化而来。我们发现，C3 H/HeJ小鼠携带的MMTV变体都是原始野生型MMTV（C3 H）（仍由C3 H/HeN株携带）与两种C3 H亚株中存在的内源性Mtv 1之间的重组体。这些重组病毒已经完全丧失了在所有C3 H小鼠中引起乳腺肿瘤的能力，而野生型MMTV（C3 H）在来自任一品系的小鼠中具有高度致瘤性。显然，肿瘤诱导能力的丧失是基于病毒基因组的改变。使用一组嵌合病毒，肿瘤减毒序列已映射到gag基因的衣壳（CA）结构域。 重要的是，我们发现与C3 H/He小鼠相反，BALB/cJ染色的小鼠对所有MMTV变体引起的乳腺肿瘤高度敏感，从而能够分析与Gag相互作用相关的宿主基因。我们已经确定了一个暂时称为“乳腺肿瘤易感性”或mts的单一基因，它定位于14号染色体，控制着GAG依赖性肿瘤易感性。 我们假设，除了众所周知的MMTV诱导的肿瘤发生机制，即插入诱变，MMTV gag编码的蛋白质也直接有助于乳腺上皮细胞的转化，通过与细胞蛋白Mts（直接或间接）合作，以增加病毒的致癌潜力。本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。 与公共卫生的相关性：这些研究将为深入了解乳腺肿瘤发生的信号转导通路提供基础，并最终有助于确定抗肿瘤化疗的潜在靶点。