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作为一种细胞周期调控因子，间接参与细胞周期机制 某些特定细胞类型中的负调控因子通过其相互作用 与转录因子E2F等细胞蛋白结合。这个 PRb在抑制增殖中的重要性从以下几个方面得到证明 几种致癌人类DNA病毒编码的必要性 功能性癌蛋白，可以有效地结合和隔离pRb， 以便在感染细胞中诱导转化的表型。这个 PRb与病毒癌蛋白及E2F发生相互作用 在PRB的一个特定的“口袋区域”。该口袋区域由以下人员共享 另外两个E1a相关蛋白，并导致了鉴定 在RB家族的蛋白质中，pRb，p107，以及我们 最近克隆了pRb2/p130。P107和p107的功能研究进展 PRb2/PL30已经表明，虽然RB家族成员可能能够 为了相互补充，蛋白质的功能并不是完全的 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形成络合物。然而，这些复合体的时间顺序 队形似乎各不相同。没有证据支持这一观点 P107通常是一种肿瘤抑制因子。此外，该表达式 视网膜母细胞瘤细胞系中p107的表达表明 P107不能弥补pRb的缺失，不能抑制肿瘤 队形。然而，pRb2/p130已经被定位到人类染色体上 16q12.2，在几个人类中发现了缺失的区域 支持rb2/p130基因参与的肿瘤 在人类癌症中作为一种肿瘤抑制基因。这样做的目的是 建议如下：(1)评估pRb2/p130在细胞内的作用 增殖和肿瘤发生。(2)分析Rb2/p130在生长过程中的变化 细胞停滞与凋亡在发育过程中的耦合或非耦合 末端分化程序。(3)研究相互作用 Rb2/p130与IGF-1途径在转录和转录水平的关系 转录后修饰。(4)调查两国之间的相互作用 带有Myb家族基因的pRb2/p130。

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.