MODULATION OF PRB2/P130 MEDIATED GROWTH SUPPRESSION

PRB2/P130 调节介导的生长抑制

• 批准号: 6512980
• 负责人: Antonio Giordano
• 金额: $ 30.51万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512980
• 关键词: Retroviridae; carcinogenesis; cell cycle; cell growth regulation; cell line; flow cytometry; gene expression; gene mutation; hamsters; human tissue; lung neoplasms; neoplasm /cancer genetics; neoplastic process; oncoproteins; phosphorylation; protein structure function; retinoblastoma protein; transfection; transfection /expression vector; tumor suppressor genes; virus protein

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.

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 共享一个特定的功能域，称为 “口袋”结构。口袋区域负责许多已知的 与特定功能相关的蛋白质-蛋白质相互作用，其中 这些分子都参与其中。所有三个家庭成员均已被证明 是生长抑制性核磷蛋白，其磷酸化状态 以细胞周期依赖性方式进行调节。每个的异位表达 家族成员的减少会导致敏感细胞的 G1 期生长停滞。这 Rb 家族在抑制增殖中的重要性是有证据的 由于需要编码多种致癌人类 DNA 病毒 癌蛋白（E1A、T 抗原和 E7）可有效结合并 隔离 Rb 家族成员以引发转化表型 被感染的细胞。人类 Prb2/p130 基因映射到 16q12.2，这是一个被发现的区域 在一些人类肿瘤中被删除。 pRb2/p130 与 几种人类癌症（包括肺癌）的发病机制和进展 癌症，表明pRb2/p130基因可能是抑癌基因 像RB一样。尽管它们有许多相似之处，但它正在变得 越来越清楚的是，尽管 Rb 家族成员可能能够 它们相辅相成，在功能上并不完全冗余。每一个 Rb 家族成员与不同的功能相关联并调节其功能 E2F转录因子家族的成员在时间调节 日程。 T98G 人胶质母细胞瘤细胞系对 pRb 和 p107 的影响，但受到 pR2/p130 的生长停滞， 表明 pRb2/p130 不仅仅是 pRb 或 p107 的替代品 并且在具体机制上存在根本差异 三个家庭成员采用的生长抑制措施。此外， 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，表明不同的 机制可能是 pRb2/p130 功能调节的基础 证明不能使用 Rb 模型来推测 pRb2/p130 磷酸化的意义和调节。的目标 该提案如下： 一个。为了定义 pRb2/p130 采用的生长抑制机制， 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.制备用于体内研究 pRB2/p130 的病毒模型。