Signaling Pathways in Proliferation and Differentiation

描述（由申请人提供）：视网膜母细胞瘤肿瘤抑制基因产物pRb调节细胞周期进程，这是其肿瘤抑制功能之一。pRb也是许多分化程序中的关键参与者;然而，没有令人信服的遗传或体内证据表明pRb在控制细胞分化中的作用有助于其肿瘤抑制功能。与Rb一样，三种ras原癌基因调节分化和增殖。Rb和ras共同作用以控制小鼠的分化。 K-ras的杂合性或N-ras的非杂合性（i）通过影响分化而不是增殖来挽救许多Rb缺陷胚胎的发育缺陷，（ii）显著提高Rb杂合子中产生的垂体腺癌的分化程度，导致其存活时间延长。总之，这些观察结果表明pRb影响分化的能力是其肿瘤抑制功能的一个方面。 Rb+/-小鼠也发生髓样（C细胞）甲状腺腺瘤。相比之下，Rb N-ras杂合子发展为转移性C细胞癌，其中一部分显示剩余N-ras等位基因的丢失。这种违反直觉的观察可能是合理的观察，神经内分泌起源的肿瘤很少显示突变的ras和引入致癌的Ras到来自这样的肿瘤细胞系促进其分化。将要进行的研究使用实验测定来检查N-ras的丢失如何有助于大的原发性甲状腺肿瘤及其相关转移的发展。Rb N-ras突变动物中产生的C细胞肿瘤的转移行为可能与胚胎发生过程中C细胞所具有的正常迁移和侵袭行为的获得有关，这一可能性将被探讨。第二条研究路线将解决转化中对不同ras亚型的要求。具体而言，K-和N-ras在SV 40 T抗原介导的鼠胚胎成纤维细胞转化中的作用将得到解决。第三条线的调查是出于观察Rb ras突变动物的骨骼肌继续显示正在进行的增殖的证据，尽管在分化的救援。详细的研究将集中在这里的分子机制，pRb和肌源性因子，MyoD，维持终末细胞周期阻滞在肌源性分化，重点是已知参与细胞周期重新进入的基因的调节。

DESCRIPTION (provided by applicant): The retinoblastoma tumor suppressor gene product, pRb, regulates cell cycle progression, and this represents one of its tumor suppressor functions. pRb is also a key participant in a number of differentiation programs; however, there is no compelling genetic or in vivo evidence that pRb's role in the control of cellular differentiation contributes to its tumor suppressor function. Like Rb, the three ras proto-oncogenes regulate differentiation and proliferation. Rb and ras function together to control differentiation in the mouse. Heterozygosity for K-ras or nullizygosity for N-ras (i) rescues many of the developmental defects that characterize Rb-deficient embryos by affecting differentiation, but not proliferation and (ii) significantly enhances the degree of differentiation of pituitary adenocarcinomas arising in Rb heterozygotes, leading to their prolonged survival. Together, these observations suggest that the ability of pRb to affect differentiation is a facet of its tumor suppressor function. Rb+/- mice also develop medullary (C-cell) thyroid adenomas. By contrast, Rb N-ras heterozygotes develop metastatic C-cell carcinomas, with a fraction of these showing loss of the remaining N-ras allele. This counterintuitive observation might be rationalized by the observations that tumors of neuroendocrine origin rarely display mutations in ras and introduction of oncogenic Ras into lines derived from such tumors promotes their differentiation. Research to be conducted examines how loss of N-ras contributes to the development of large primary thyroid tumors and their associated metastases using experimental assays. The possibility that the metastatic behavior of C-cell tumors arising in Rb N-ras mutant animals might be associated with acquisition of the normal migratory and invasive behavior C-cells possess during embryo genesis will be explored. A second line of research will address the requirement for different ras isoforms in transformation. Specifically, the role of K- and N-ras in SV40 T antigen-mediated transformation of murine embryo fibroblasts will be addressed. A third line of investigation is motivated by the observation that skeletal muscle in Rb ras mutant animals continues to display evidence of ongoing proliferation, despite a rescue in differentiation. Detailed research will be focused here on the molecular mechanism by which pRb and the myogenic factor, MyoD, maintain a terminal cell cycle arrest during myogenic differentiation, with emphasis on the regulation of genes known to participate in cell cycle re-entry.