SIGNALING PATHWAYS INVOLVED IN PROLIFERATION

视网膜母细胞瘤基因Rb是典型的肿瘤抑制基因。Rb基因失活与多种人类癌症有关。Rb基因缺陷的小鼠在子宫中死亡，这表明视网膜母细胞瘤基因产物pRb在发育中具有关键作用。对pRb在发育和癌症中的作用还没有完全的了解。RAS蛋白--H-Ras、K-Ras4a、K-Ras4b和N-Ras--是由人类癌症中最频繁突变的原癌基因编码的。对小鼠的遗传分析表明，某些RAS成员对发育很重要。因此，pRb和ras在发育和癌症中都起着关键作用。众所周知，这些蛋白质的功能是相互联系的。PRb已被认为是RAS介导的有丝分裂信号的最终下游靶点。在这方面，几乎所有关于RAS信号的研究都与信息从细胞表面到细胞核的单向流动有关。我们实验室最近的初步数据表明，pRb可以反过来调节RAS的活性，这表明核质信号是双向的。拟议研究的总体目标是研究公共广播如何对资源需求产生影响。了解这两种蛋白之间的双向通讯将为研究pRb和ras在癌症发生和发展中的作用提供新的见解。这项工作将研究PRB介导的RAS活性抑制的遗传决定因素。将努力确定和表征连接PRB和RAS的通路中的成分(S)。本研究将探讨PRB后RAS活性升高对体外和小鼠的生物学意义。这里的重点将放在确定pRb介导的RAS调节对小鼠发育和肿瘤转化的贡献。

The retinoblastoma gene, Rb, is the prototypical tumor suppressor. Inactivation of the Rb gene has been implicated in a variety of human cancers. Rb-deficient mice die in utero, suggesting that the retinoblastoma gene product, pRb, has an critical role in development. A complete understanding of the role of pRb in development and cancer does not exist. The Ras proteins-H-Ras, K-Ras4a, K-Ras4b, and N-Ras-are encoded by the most frequently mutated proto-oncogenes in human cancer. Genetic analysis in the mouse indicate that certain Ras members are important for development. Thus, both pRb and Ras play key roles in development and cancer. The function of these proteins is known to be connected. pRb has been identified as an ultimate downstream target of Ras-mediated mitogenic signaling. In this regard, virtually all studies focused on Ras signaling pertain to the unidirectional flow of information from the cell surface to the nucleus. Recent preliminary data from our laboratory suggests that pRb can in turn regulate Ras activity, suggesting that nuclear-cytoplasmic signaling is bidirectional. The broad objective of the proposed research is to examine how pRb exerts its effect on Ras. An understanding of the bi-directional communication between these two proteins will provide new insights into the role of both pRb and Ras in cancer and development. The work will examine the genetic determinants of pRb-mediated suppression of Ras activity. An effort will be made to identify and characterize the component(s) in the pathway connecting pRb and Ras. The research will explore the biological significance of elevated Ras activity following pRb to both in vitro and in the mouse. Focus here will be placed on defining the contribution of pRb-mediated regulation of Ras to murine development and neoplastic transformation.