MOLECULAR CHARACTERIZATION OF A MEMBER OF THE RB FAMILY

RB 家族成员的分子表征

• 批准号: 6237267
• 负责人: Antonio Giordano
• 金额: $ 22.03万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-22 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237267
• 关键词: apoptosis; carcinogenesis; cell cycle; cell line; cell proliferation; developmental genetics; insulinlike growth factor; oncoproteins; posttranscriptional RNA processing; protooncogene; retinoblastoma protein; transcription factor; tumor suppressor genes

Many forms of human malignancies have been linked to mutations in the tumor suppressor gene retinoblastoma, RB. The nuclear phosphoprotein, pRb, is involved indirectly in the cell cycle machinery by serving as a negative regulator in some specific cell types through its interactions with cellular proteins such as the transcription factor E2F. The importance of pRb in the inhibition of proliferation is evidenced by the necessity of a number of oncogenic human DNA viruses to encode functional oncoproteins, which can effectively bind and sequester pRb, in order to elicit a transformed phenotype in infected cells. The interaction of pRb with the viral oncoproteins as well as to E2F occurs at a specific "pocket region" in pRb. This pocket region is shared by two additional E1A associated proteins and has lead to the identification of the Rb-family of proteins, pRb, p107 and the newest member that we have recently cloned, pRb2/ p130. Recent functional studies of p107 and pRb2/pl30 have indicated that while the Rb-family members may be able to complement each other the proteins are not fully functionally redundant. Like pRb, ectopic expression of p107 is able to suppress the growth of certain cell lines. Additionally, pRb, p107, and p130/pRb2 form complexes with E2F. However, the temporal order of the complexes formation appears to vary. There is no evidence to support the notion that p107 is normally a tumor suppressor. Furthermore, the expression of p107 in cell lines derived from retinoblastoma tumors implies that p107 is unable to complement the lack of pRb and to suppress tumor formation. pRb2/p130, however, has been mapped to human chromosome 16q12.2, an area in which deletions have been found in several human neoplasias which is in support of an involvement of the RB2/p130 gene in human cancer as a tumor suppressor gene. The goals of this proposal are thus: (1) To assess the role of pRb2/p130 in cellular proliferation and tumorigenesis. (2) To analyze Rb2/p130 during growth arrest and apoptosis either coupled or uncoupled from the developmental program of terminal differentiation. (3) To investigate the interactions of Rb2/p130 with the IGF-1 pathway with regard to transcriptional and post-transcriptional modifications. (4) To investigate the interactions of pRb2/p130 with the Myb-family genes.

许多形式的人类恶性肿瘤都与基因突变有关 肿瘤抑制基因视网膜母细胞瘤，RB。 核磷蛋白， pRb 间接参与细胞周期机制 通过其相互作用在某些特定细胞类型中发挥负调节作用 与转录因子 E2F 等细胞蛋白结合。 这 pRb 在抑制增殖中的重要性由 许多致癌人类 DNA 病毒编码的必要性 功能性癌蛋白，可有效结合并隔离pRb， 以引起受感染细胞表型的转化。 这 pRb 与病毒癌蛋白以及 E2F 发生相互作用 在 pRb 的特定“口袋区域”。 该口袋区域由以下人员共享 两个额外的 E1A 相关蛋白并导致了鉴定 Rb 蛋白家族的成员 pRb、p107 以及我们发现的最新成员 最近克隆了 pRb2/p130。 p107 和 p107 的最新功能研究 pRb2/pl30 表明，虽然 Rb 家族成员可能能够 为了相互补充，蛋白质的功能并不完全 多余的。 与 pRb 一样，p107 的异位表达能够抑制 某些细胞系的生长。 此外，pRb、p107 和 p130/pRb2 与E2F形成复合物。 然而，复合体的时间顺序 形成似乎有所不同。 没有证据支持这个观点 p107 通常是一种肿瘤抑制因子。 此外，表达式 p107 在视网膜母细胞瘤肿瘤细胞系中的存在意味着 p107 无法补充 pRb 的缺乏并抑制肿瘤 形成。 然而，pRb2/p130 已被定位到人类染色体 16q12.2，在几个人类中发现了该区域的缺失 支持 RB2/p130 基因参与的肿瘤 在人类癌症中作为肿瘤抑制基因。 本次活动的目标 因此建议是： (1) 评估 pRb2/p130 在细胞中的作用 增殖和肿瘤发生。 (2) 分析生长过程中的Rb2/p130 停滞和细胞凋亡与发育耦合或不耦合 终末分化程序。 (3) 相互作用研究 Rb2/p130 与 IGF-1 通路在转录和 转录后修饰。 (4) 探究相互作用 pRb2/p130 与 Myb 家族基因。