Tumor Susceptibility Gene 101 Deficiency and Neoplasia

我们的长期目标是确定调节乳腺组织细胞生长和肿瘤转化的机制。我们目前的研究集中在肿瘤易感基因101（TSG 101）如何防止乳腺上皮细胞的肿瘤发生。TSG101最近被鉴定为在鼠细胞系中生长限制和维持基因组稳定性的重要因子。该基因编码的蛋白质在人类和啮齿类动物之间具有非常高的相似性。虽然TSG 101的染色体缺失是罕见的事件，但在人类癌症中经常观察到异常转录物。尽管TSG101在维持培养细胞基因组完整性方面具有重要作用，但其在体内的生物学功能在很大程度上尚不清楚。该提案的具体目的是确定TSG101在体内正常发育和肿瘤发生过程中的作用。我们使用在乳腺组织中携带TSG101体细胞突变的基因工程小鼠。 我们将研究TSG101是否具有肿瘤抑制基因或乳腺组织的特征。TSG101内介导其在肿瘤发生过程中的作用的关键结构域将通过用缺乏蛋白质特定部分的较短TSG101突变体替换内源性TSG1021蛋白来确定。最后，我们将研究TSG101作为DNA甲基转移酶1靶向转录抑制的辅助因子的作用。TSG101可能在各种不同的途径中发挥作用，这些途径对生长，分化和癌症进展至关重要。因此，研究TSG101表达的调控及其生物学功能将为我们提供新的见解，使我们能够拦截致癌途径，这需要足够水平的这种蛋白质才能正常发挥作用。

Our long-term objective is to determine the mechanisms that regulate cellular growth and neoplastic transformation in breast tissue. Our current studies focus on how the tumor susceptibility gene 101 (TSG101) prevents tumorigenesis in mammary epithelial cells. TSG101 has been recently identified as an important factor for growth restriction and maintenance of genome stability in murine cell lines. The protein encoded by this gene has a very high similarity between human and rodents. Although chromosomal deletions of TSG 101 are rare events, aberrant transcripts are observed quite frequently in human cancers. Despite its important role for the maintenance of genome integrity in cultured cells, the biological function of TSG101 in vivo is largely unknown. The specific aims of this proposal are to determine the role of TSG101 during normal development and tumorigenesis in vivo. We use genetically engineered mice that carry somatic mutation for TSG101 in mammary tissue. We will investigate whether TSG101 has characteristics of a tumor suppressor gene or mammary tissue. The critical domains within TSG101 that mediate its role during tumorigenesis will be determined by replacing the endogenous TSG1021 protein with shorter with shorter TSG101 mutants that lack specific parts of the protein. Finally, we will investigate the suggested role of TSG101 as a co-factor for the transcriptional repression of targeted by DNA methyltransferase 1. TSG101 might function in various different pathways that are important for growth, differentiation, and cancer progression. Thus, investigating the regulation of TSG101 expression and its biological function will provide us with new insights that will allow us to intercept oncogenic pathways, that require adequate levels of this protein to function normally.