ABELSON LEUKEMIA VIRUS TRANSFORMATION

Abelson小鼠白血病病毒（Ab-MLV）诱导快速前B细胞淋巴瘤 并转化前B细胞和一些已建立的啮齿动物成纤维细胞 体外这种病毒携带v-abl癌基因， 癌基因的非受体蛋白酪氨酸激酶（PTK）家族， 转化由v-Abl蛋白的PTK活性介导 由Ab-MLV编码。然而，这种活动本身并不能解释独特的 对Ab-MLV的细胞反应谱。蛋白质的其他特征 是决定感染结果的关键重要v-Abl 域已被定义，但这些区域的机制 协调生长和分化的变化，导致从抗体- MLV感染在很大程度上是未知的。富含脯氨酸的羧基末端 分子是Abl蛋白所特有的，在Abl蛋白中起着重要但很差的作用。 在淋巴细胞转化中的作用。SH2结构域a 与酪氨酸磷酸化部分相互作用的区域似乎 影响对转化敏感的细胞类型。转型 淋巴样细胞的恶性生长和分化 逮捕了Ab-MLV突变体的实验表明，不同的途径 这两种现象的中介。然而，我们对电路的理解， 这种和其他对v-Abl表达的反应并不好发生- 开发这里提出的工作重点是了解这些 提出四个问题：l。COOH中的哪些序列 v-Abl蛋白末端增强淋巴转化？2.怎么 Ras通路和其他通路的信号介导了 羧基末端对淋巴细胞转化的影响？3. SH2中的序列如何 v-Abl蛋白结构域与Shc相互作用，Shc是一种衔接蛋白， 与Grb2/Sos相互作用，它们如何调节转化？4.什么 途径介导v-Abl诱导的分化停滞？的信息 获得应该进一步我们了解的特点，控制 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 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.