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，这代表了其肿瘤抑制功能之一。pRb也是许多差异化项目的关键参与者；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原癌基因调控分化和增殖。在小鼠中，Rb和ras共同起着控制分化的作用。K-ras的杂合性或N-ras的零合性(i)通过影响分化而不是增殖来挽救Rb缺陷胚胎的许多发育缺陷；（ii）显著提高Rb杂合子中垂体腺癌的分化程度，从而延长其生存时间。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。

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.