Ras signaling in leukemogenesis

白血病发生中的 Ras 信号传导

• 批准号: 7360320
• 负责人: Ruibao Ren
• 金额: $ 34.1万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7360320
• 关键词: Acute Myelocytic Leukemia; Acute Myelomonocytic Leukemia; Alleles; Biochemical; Biological; Biological Assay; Bone Marrow; Cell Communication; Cell Proliferation; Cell membrane; Cells; Chronic Myelomonocytic Leukemia; Complex; Cultured Cells; Development; Disease; Environment; Enzymes; Event; Genes; Goals; Hematologic Neoplasms; Hematopoietic; Knock-out; Knockout Mice; Laboratory Study; Mediating; Membrane; Methylation; Modeling; Modification; Molecular; Mus; Mutation; Myeloid Leukemia; Myeloproliferative disease; Oncogene Proteins; Oncogenic; Output; Play; Post-Translational Protein Processing; Process; Relative (related person); Reporting; Rest; Role; Signal Transduction; Site; Solid Neoplasm; Testing; Therapeutic Intervention; Transplantation; cancer therapy; cell type; farnesylation; farnesyltranstransferase; improved; in vivo; leukemia; leukemogenesis; metaplastic cell transformation; mouse model; mutant; palmitoylation; protein farnesyltransferase; protein-S-isoprenylcysteine O-methyltransferase; ras Proteins; tumorigenesis

DESCRIPTION (provided by applicant): Ras proteins are crucial regulators of cell proliferation, survival and differentiation. Aberrant activation of Ras proteins, either by Ras mutations or by altering genes that directly or indirectly regulate Ras, is common in both solid tumors and hematologic malignancies. Ras proteins can interact with a wide spectrum of Ras effectors that play either positive or negative roles in the control of cell proliferation and survival. The association with different microdomains of the plasma membrane as well as other internal cell membranes may allow different Ras proteins to access to different pools of Ras effectors and to generate distinct signal outputs. In the past, laboratory studies of the roles of Ras effectors in oncogenesis have been performed mostly in cultured cells. And even in these assays, cellular transformation of different cell types was shown to require different Ras effectors. Leukemogenesis is a complex process that not only involves the effects of oncogenic mutation(s) within the target cells, but interactions of such cells with the rest of the in vivo environment. The overall hypothesis of this proposal is that the in vivo leukemogenesis by oncogenic Ras may involve unique Ras signaling networks. We have previously examined the leukemogenicity of oncogenic N-Ras using an improved mouse bone marrow transduction and transplantation model and found that oncogenic N-Ras efficiently induced myeloproliferative disorder and acute myelogenous leukemia-like disease in mice. We will use this mouse model to test the hypothesis stated above by examining the roles of various post-translational modifications and effectors of Ras in N-Ras leukemogenesis. The specific aims for this proposal are: 1. To determine the roles of post-translational modifications of N-Ras in leukemogenesis by a mutational analysis of the modification sites of oncogenic N-Ras, as well as by analyzing N-Ras leukemogenesis in mice with conditional knockout alleles of Reel or Icmt (genes encoding the Ras converting enzyme and isoprenylcysteine carboxyl methyltransferase, respectively). 2. To determine the roles of downstream effectors of Ras in N-Ras leukemogenesis by a combination of biological and biochemical approaches, using effector domain mutants of the oncogenic N-Ras, as well as activated and inhibitory forms of various effectors of Ras. The ultimate goal of these studies is to identify critical molecular events in Ras leukemogenesis, allowing therapeutic interventions of leukemias involving Ras.

描述（由申请人提供）：RAS蛋白是细胞增殖，生存和分化的关键调节剂。通过RAS突变或通过直接或间接调节Ras的基因的异常激活在实体瘤和血液学恶性肿瘤中都是常见的。 RAS蛋白可以与广泛的RAS效应子相互作用，这些RAS效应子在控制细胞增殖和存活中起着阳性或负作用。与质膜以及其他内部细胞膜的不同微区域的关联可能使不同的RAS蛋白可以访问不同的RAS效应子池并产生不同的信号输出。过去，关于RAS效应子在肿瘤发生中作用的实验室研究主要是在培养的细胞中进行的。即使在这些测定中，不同细胞类型的细胞转化也被证明需要不同的RAS效应子。白血病是一个复杂的过程，不仅涉及靶细胞内致癌突变的作用，而且还涉及此类细胞与其余体内环境的相互作用。该提议的总体假设是，致癌性RAS的体内白血病发生可能涉及独特的RAS信号网络。我们先前使用改进的小鼠骨髓转导和移植模型检查了致癌N-RAS的白血病性，并发现致癌N-RAS在小鼠中有效诱导了脊髓增生性疾病和急性脊髓脊髓性白血病样疾病。我们将使用该小鼠模型来检验上述假设，通过研究RAS在N-RAS白血病发生中的各种翻译后修饰和效应子的作用。该提案的具体目的是：1。通过对致癌N-RAS的修饰位点的突变分析以及通过分析小鼠N-RAS白细胞发育作用，以确定N-RAS在白血病发生中的翻译后修饰的作用。使用卷轴或ICMT的条件基因敲除等位基因（编码RAS转化酶和异位肾上腺半胱氨酸羧基甲基转移酶的基因）。 2。通过结合生物学和生物化学方法的结合，使用了致癌n-Ras的效应域突变体，以及RAS的各种效应子的激活和抑制形式。这些研究的最终目的是确定RAS白血病发生中的关键分子事件，从而使涉及RA的白血病的治疗干预措施。