PRODUCTS OF THE TRANSFORMING GENES OF POLYOMAVIRUS

多瘤病毒可引起多种肿瘤。因为它需要 细胞S期复制，多发瘤进化机制多样 转化基因产物(T抗原)通过哪些途径促进细胞周期 进步。由于这些机制针对的是正常细胞成分 增长控制，这里获得的信息通常与 肿瘤问题。这项工作涉及三个方面的每一个 转化基因产品。一种N端J结构域通用的全3T 抗原将它们连接到伴侣系统。J函数显然是 对于不同的T抗原是不同的。它调节Rb肿瘤抑制因子 通过J依赖和J非依赖机制；实验将 确定LT影响的RB系列功能的范围 机制。J失活所需的RB中的序列为 下定决心。在p130上的实验，RB家族成员与 细胞周期退出将决定其发生的基础和后果 它诱导了磷酸化。我们将对其结构和功能进行探讨 比较大T(LT)和小T(ST)中的J结构域以区分序列 肿瘤抑制因子的大T(LT)调节所需 视网膜母细胞瘤易感性(RB)基因家族 小T(ST)对蛋白磷酸酶2A(PP2A)的调节作用这个 J结构域结构对病毒复制的贡献将是 被解剖了。将测试细胞J结构域，以确定它们是否 调节正常细胞基因表达。LT中的新函数 调控细胞生长和基因表达的图谱将被绘制出来，它们的 细胞目标已确定。大的T磷酸化位点将是 确定和测试以确定它们是否规范相互作用 肿瘤抑制因子的作用。中T(MT)是肿瘤的关键 归纳法。将绘制酪氨酸磷酸化的新位点图，并 它们的功能通过突变进行了测试。相互作用的细胞蛋白质 这些地点将会确定。因为MT有能力引起 肿瘤和促进细胞存活的相互作用是密切相关的 磷脂酰肌醇3-激酶(PI3K)与MT之间的联系 功能与新发现的肌醇起始靶点--PDK1 磷脂，将被检测。

Polyomavirus causes a broad spectrum of tumors. Because it requires cellular S phase to replicate, polyoma has evolved diverse mechanisms by which transforming gene products (T antigens) promote cell cycle progression. Since these mechanisms target normal cell components of growth control, information gained here is generally relevant to the problem of neoplasia. This work involves aspects of each of the 3 transforming gene products. An N-terminal J domain common all 3 T antigens connects them to chaperone systems. J function is clearly different for different T antigens. LT regulates Rb tumor suppressors by both J dependent and J independent mechanisms; experiments will determine the range of Rb family functions that LT affects by each mechanism. Sequences in Rb required for J inactivation will be determined. Experiments on p130, an Rb family member associated with cell cycle withdrawal will determine the basis for, and consequences of LT induced phosphorylation. We will probe the structure and function of J domains in large T(LT) and small T(ST) to differentiate sequences required for large T(LT) regulation of tumor suppressors of the retinoblastoma susceptibility (Rb) gene family from those connected to small T(ST) regulation of protein phosphatase 2A(PP2A). The contributions of the J domain structure to virus replication will be dissected. Cellular J domains will be tested to determine whether they regulate normal cellular gene expression. Novel functions in LT that regulate cell growth and gene expression will be mapped, and their cellular targets determined. Large T phosphorylation sites will be determined and tested to determine whether they regulate interactions with the tumor suppressors. Middle T (MT) is critical for tumor induction. Novel sites of tyrosine phosphorylation will be mapped and their function tested by mutation. The cellular proteins interacting with those sites will be determined. Since the ability of MT to cause tumors and to promote cell survival is strongly connected to interaction with phosphatidylinositol 3-kinase (PI3K), the connection between MT function and PDK1, a newly discovered initial target of inositol phospholipids, will be examined.