ABELSON LEUKEMIA VIRUS TRANSFORMATION

艾贝尔森白血病病毒转化

• 批准号: 2653959
• 负责人: NAOMI ROSENBERG
• 金额: $ 26.02万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2653959
• 关键词: 3T3 cells; Abelson leukemia virus; B cell lymphoma; B lymphocyte; DNA binding protein; DNA footprinting; biological signal transduction; cell differentiation; cell transformation; gene expression; guanine nucleotide binding protein; laboratory mouse; murine leukemia virus; mutant; northern blottings; oncogenes; oncoproteins; polymerase chain reaction; protein sequence; protein structure function; protein tyrosine kinase; site directed mutagenesis; viral leukemogenesis; virus genetics; virus protein

Abelson murine leukemia virus (Ab-MLV) induces a rapid pre-B cell lymphoma in mice and transforms pre-B cells and some established rodent fibroblasts in vitro. This virus carries the v-abl oncogene, a member of the nonreceptor protein tyrosine kinase (PTK) family of oncogenes and transformation is mediated by the PTK activity of the v-Abl protein encoded by Ab-MLV. However this activity alone does not explain the unique spectrum of cellular responses to Ab-MLV. Other features of the protein are critical in determining the outcome of infection. Important v-Abl domains have been defined but the mechanisms by which these regions orchestrate the changes in growth and differentiation that result from Ab- MLV infection are largely unknown. The proline rich COOH terminus of the molecule is unique to Abl proteins and plays an important but poorly understood role in transformation of lymphoid cells. The SH2 domain a region that interacts with tyrosine phosphorylated moieties appears to influence the types of cells susceptible to transformation. Transformation of lymphoid cells involves both malignant growth and differentiation arrest. Experiments with Ab-MLV mutants suggest that distinct pathways mediate these two phenomena. However, our understanding of the circuits by which this and other responses to expression of v-Abl occurs is not well- developed. The work proposed here focuses on understanding these mechanisms by asking four questions: l. What sequences within the COOH terminus of v-Abl protein enhance lymphoid transformation? 2. How do signals to the Ras pathway and other pathways mediate the effects of the COOH terminus on lymphoid cell transformation? 3. How do sequences in SH2 domain of v-Abl protein interact with Shc an adaptor protein that interacts with Grb2/Sos and how do they modulate transformation? 4. What pathways mediate v-Abl induced differentiation arrest? The information obtained should further our understanding of the features that control the response to infection with this virus and also contribute to a broader understanding of the mechanisms by which abl and other oncogenes induce malignant disease.

Abelson 鼠白血病病毒 (Ab-MLV) 诱导快速前 B 细胞淋巴瘤 在小鼠中转化前 B 细胞和一些已建立的啮齿动物成纤维细胞 体外。该病毒携带 v-abl 癌基因，该基因是 非受体蛋白酪氨酸激酶 (PTK) 癌基因家族和 转化由 v-Abl 蛋白的 PTK 活性介导 由 Ab-MLV 编码。然而，仅此活动并不能解释独特的 Ab-MLV 的细胞反应谱。蛋白质的其他特征 对于确定感染的结果至关重要。重要的 v-Abl 域已经被定义，但是这些区域的机制 协调由抗体引起的生长和分化的变化 MLV 感染很大程度上是未知的。富含脯氨酸的 COOH 末端 该分子是 Abl 蛋白所特有的，发挥着重要但作用不大的作用。 了解淋巴细胞转化中的作用。 SH2域a 与酪氨酸磷酸化部分相互作用的区域似乎 影响易发生转化的细胞类型。转型 淋巴细胞的恶性生长和分化 逮捕。 Ab-MLV 突变体的实验表明，不同的途径 调解这两种现象。然而，我们对电路的理解 这种反应和其他对 v-Abl 表达的反应发生的情况并不好- 发达。这里提出的工作重点是理解这些 通过提出四个问题来建立机制： l． COOH 内有哪些序列 v-Abl蛋白末端增强淋巴转化？ 2. 怎么做 Ras 通路和其他通路的信号介导 淋巴细胞转化中的COOH末端？ 3. SH2中的序列如何 v-Abl 蛋白的结构域与 Shc 一种接头蛋白相互作用， 与 Grb2/Sos 相互作用以及它们如何调节转化？ 4. 什么 途径介导 v-Abl 诱导的分化停滞？信息 所获得的应该进一步我们对控制特征的理解 对这种病毒感染的反应，也有助于更广泛的 了解 abl 和其他癌基因诱导的机制 恶性疾病。