MODULATION OF PRB2/P130 MEDIATED GROWTH SUPPRESSION

视网膜母细胞瘤基因家族目前由三个成员组成：pRb， p107和pRb 2/p130，它们共享一个特定的功能结构域，称为 “口袋”结构。口袋区是许多已知的 特定功能相关蛋白质-蛋白质相互作用，其中 这些分子参与其中。所有三个家庭成员都被证明 是其磷酸化状态 是以细胞周期依赖性方式调节的。异位表达 导致敏感细胞的G1期生长停滞。的 Rb家族在抑制增殖中的重要性是证据 由于需要大量致癌的人类DNA病毒来编码 癌蛋白（E1 A，T抗原和E7），可以有效地结合， 隔离Rb家族成员，以引发转化的表型， 被感染的细胞人类Prb 2/p130基因定位于16q12.2， 在几种人类肿瘤中缺失。pRb 2/p130参与了 包括肺癌在内的几种人类癌症的发病机制和进展 pRb 2/p130基因可能是一个抑癌基因 比如RB尽管它们有许多相似之处，但是， 越来越清楚的是，即使Rb家族成员可能能够 虽然它们是互补的，但它们在功能上并不完全冗余。中的每 Rb家族成员与不同的细胞因子相关并调节其功能， E2 F转录因子家族的成员在时间调节的 schedule. T98 G人胶质母细胞瘤细胞系对免疫抑制剂是难治的。 pRb和p107的作用，但经历来自pR 2/p130的生长停滞， 表明pRb 2/p130不仅是pRb或p107的替代物， 而且在具体的机制上有根本的不同， 三个家族成员使用的生长抑制。此外，本发明还 与pRb不同，pRb 2/p130的磷酸化形式是优选的靶点 的DNA肿瘤病毒癌蛋白E1 A，这表明，不同的 可能是pRb 2/p130功能调节的基础， 这表明人们不能用Rb模型来推测 pRb 2/p130磷酸化的意义及其调节。的目标 因此，这项建议是： a.为了定义pRb 2/p130所采用的生长抑制机制， B.为了了解pRb 2/p130磷酸化的调节功能， C.目的探讨Rb 2/p130基因在肺癌中的作用 发展和进步， D.目的制备pRB 2/p130病毒模型，为pRB 2/p130的体内研究奠定基础。

The retinoblastoma gene family currently consists of three members: pRb, p107, and pRb2/p130, that share a particular functional domain termed the "pocket" structure. The pocket region is responsible for many of the known specific functionality relevant protein-protein interactions in which these molecules are involved. All three family members have been shown to be growth suppressive nuclear phosphoproteins whose phosphorylation status is regulated in a cell cycle dependent manner. Ectopic expression of each of the family members leads to G1-growth arrest of sensitive cells. The importance of the Rb family in the inhibition of proliferation is evidence by the necessity of a number of oncogenic human DNA viruses to encode oncoproteins (E1A, T-antigen, and E7) which can effectively bind and sequester the Rb-family members to elicit a transformed phenotype in infected cells. The human Prb2/p130 gene maps to 16q12.2, a region found deleted in several human neoplasia. pRb2/p130 has been implicated in the pathogenesis and progression of several human cancers, including lung cancer, suggesting that the pRb2/p130 gene may be a tumor suppressor gene like RB. Despite their many similarities, however, it is becoming increasingly clear that even though the Rb family members may be able to complement each other, they are not fully functionally redundant. Each of the Rb family members associate with and modulate the function of distinct members of the E2F transcription factor family in a temporally modulated schedule. The T98G human glioblastoma cell line is refractory to the effects of pRb and p107 but undergoes growth arrest from pR2/p130, indicating the pRb2/p130 is not merely a surrogate for either pRb or p107 and that there are fundamental differences in the specific mechanisms of growth inhibition employed by the three family members. Additionally, unlike pRb, the phosphorylated form of pRb2/p130 is the preferred target of the DNA tumor viral oncoprotein E1A, suggesting that a different mechanism may underlie the functional regulation of pRb2/p130 and demonstrating that one can not use the Rb model to speculate the significance and regulation of phosphorylation of pRb2/p130. The goals of this proposal are thus: a. To define the growth inhibitory mechanism(s) employed by pRb2/p130, b. To understand the regulatory function of pRb2/p130 phosphorylation, c. To define the role of the Rb2/p130 gene in human lung cancer development and progression, d. To prepare viral models for studying pRB2/p130 in vivo.