MOLECULAR CHARACTERIZATION OF A MEMBER OF THE RB FAMILY

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。 核磷蛋白， pRb通过作为一种蛋白质间接参与细胞周期机制， 在某些特定的细胞类型中，通过其相互作用， 与细胞蛋白质如转录因子E2 F结合。 的 pRb在抑制增殖中的重要性由以下证明： 许多致癌的人类DNA病毒必须编码 功能性癌蛋白，其可以有效地结合和隔离pRb， 以在感染细胞中引发转化表型。 的 pRb与病毒癌蛋白以及E2 F发生相互作用 在pRb中的特定“口袋区域”。 该口袋区域由 两个额外的E1 A相关蛋白，并导致鉴定 Rb蛋白家族的成员pRb，p107和我们发现的最新成员， 最近克隆了pRb 2/ p130。 p107蛋白的功能研究进展 pRb 2/p130已经表明，虽然Rb家族成员可能能够 为了相互补充，这些蛋白质在功能上并不完全 多余 与pRb一样，p107的异位表达能够抑制细胞凋亡， 某些细胞系的生长。 此外，pRb、p107和p130/pRb 2 与E2 F形成复合物。 然而，复合物的时间顺序 形成似乎各不相同。 没有证据支持这种观点 p107通常是肿瘤抑制因子 此外，表达式 p107在视网膜母细胞瘤细胞系中的表达表明， p107不能补充pRb的缺失，不能抑制肿瘤的发生 阵 然而，pRb 2/p130已经定位于人类染色体上， 16q12.2，一个在几个人类中发现缺失的区域， 支持RB 2/p130基因参与的肿瘤 作为一种肿瘤抑制基因。 这个的目标 因此，我们提出以下建议：（1）研究pRb 2/p130在细胞内的作用， 增殖和肿瘤发生。 (2)在生长过程中分析Rb 2/p130 阻滞和细胞凋亡，无论是偶联或不偶联的发展， 终端差异化方案。 (3)为了研究 Rb 2/p130与IGF-1通路在转录和 转录后修饰。 (4)为了研究 pRb 2/p130与Myb家族基因。

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.