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pRb2/p130，它们共享一个称为 “口袋”结构。口袋区域是许多已知的 与特定功能相关的蛋白质-蛋白质相互作用 这些分子都参与其中。所有三个家庭成员都被证明 BE抑制生长的核磷蛋白的磷酸化状态 是以细胞周期依赖的方式调节的。各自的异位表达 家族成员的死亡导致敏感细胞的G1期生长停滞。这个 Rb家族在抑制增殖中的重要性就是证据 由一些致癌的人类DNA病毒编码的必要性 癌蛋白(E1a、T抗原和E7)可以有效地结合和 隔离RB-家族成员以诱导转化的表型 被感染的细胞。发现人类Prb2/p130基因位于16q12.2区域 在几个人类肿瘤中被删除。PRb2/p130被认为与 包括肺癌在内的几种人类癌症的发病机制和进展 提示pRb2/p130基因可能是肿瘤抑制基因 就像RB一样。然而，尽管它们有许多相似之处，但它正在成为 越来越清楚的是，即使RB家族成员可能能够 它们是相辅相成的，在功能上并不完全多余。每一个 RB家族成员与DISTINCT的功能相关并对其进行调节 时间调控的E2F转录因子家族成员 时间表。T98G人脑胶质母细胞瘤细胞株对 PRb和p107的作用，但从pR2/p130经历生长停滞， 表明pRb2/p130不仅仅是pRb或p107的替代品 在特定的机制上有根本的不同 三个家庭成员使用的生长抑制。另外， 与pRb不同，pRb2/p130的磷酸化形式是首选靶标 DNA肿瘤病毒癌蛋白E1a的差异，表明不同的 机制可能是pRb2/p130功能调节的基础 证明人们不能使用RB模型来推测 PRb2/p130磷酸化的意义及调控。的目标 这项建议如下： A.为了定义pRb2/p130使用的生长抑制机制(S)， B.为了了解pRb2/p130磷酸化的调节功能， C.确定Rb2/p130基因在人类肺癌中的作用 发展和进步， D.制备体内研究pRB2/p130的病毒模型。

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.