ABELSON LEUKEMIA VIRUS TRANSFORMATION

Abelson鼠白血病病毒(Ab-MLV)诱导快速前B细胞淋巴瘤 在小鼠体内转化前B细胞和一些已建立的啮齿动物成纤维细胞 在试管中。这种病毒携带v-abl癌基因，是 非受体蛋白酪氨酸激酶(PTK)癌基因家族和 转化是由v-abl蛋白的ptk活性介导的。 由单抗-MLV编码。然而，这一活动本身并不能解释独特的 细胞对单抗-MLV的反应谱。蛋白质的其他特征 是决定感染结果的关键因素。重要的v-abl 已经定义了区域，但这些区域所使用的机制 协调由抗体引起的生长和分化的变化 MLV感染在很大程度上是未知的。富含脯氨酸的COOH末端 Abl分子是Abl蛋白所特有的，发挥着重要但作用不大的作用。 了解淋巴细胞转化过程中的作用。SH2结构域a 与酪氨酸磷酸化部分相互作用的区域似乎 影响易转化的细胞类型。转化 淋巴样细胞与恶性生长和分化有关 逮捕。用抗体-MLV突变体进行的实验表明，不同的途径 调停这两个现象。然而，我们对电路的理解是 发生这种和其他对v-Abl表达的反应是不好的- 发展起来的。这里提出的工作重点是理解这些 机制通过提出四个问题：L。COOH内部有哪些序列 V-Abl蛋白末端促进淋巴转化？2.如何 RAS通路和其他通路的信号介导了 关于淋巴细胞转化的COOH末端？3.SH2中的序列是如何 V-Abl蛋白的结构域与Shc-an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 介导v-Abl诱导分化停滞的通路？这些信息 应该会进一步加深我们对控制 对感染这种病毒的反应，也有助于更广泛的 对ABL和其他癌基因诱导机制的理解 恶性疾病。

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.