ROLE OF CELL CYCLE REGULATION IN TRANSFORMATION BY V-ABL AND BCR-ABL

我们已经证明，v-Abl启动了一种信号转导，导致 Ras、Raf和细胞周期蛋白依赖性激酶(CDK)的激活 随后Rb家族蛋白的过度磷酸化，激活 E2F/DP蛋白与E2F依赖基因的诱导转录 包括c-myc和DHFR。由于我们的结果显示v-Abl具有直接的 对细胞周期的影响，重要的是要充分描述v-Abl是如何 和bcr-abl影响细胞周期并评估细胞周期的重要性 对Abl依赖的转化的调控。细胞周期调节是 是增长调控的核心，因此理解这些 机制是理解Abelson分子机制的关键 转型。 在第一个特定目标中，将成纤维细胞和Preb细胞转化为 将对v-Abl的温度敏感形式进行分析，以确定v-Abl如何 ABL将被分析以确定v-Abl如何影响细胞周期 监管。细胞周期调控的三个重要方面是 研究：1)细胞周期蛋白和CDK抑制剂的浓度， 2)CDK2和CDK4活性；3)诱导E2F和c-Myc依赖 MRNAs。在特定目标II中，我们将检验v-Abl的假设 依赖于Abi-L或JAKS的信号转导影响细胞周期 监管。由Goff和Rothman小组产生的细胞系 已经检测到阿比-L或雅克的信号将与正常进行比较 细胞进行v-Abl依赖的细胞周期调控。在特定目标II中 将通过分析研究bcr-abl影响细胞周期的能力 慢性粒细胞白血病患者的原始样本和细胞系研究 转化温度敏感型BCR-ABL。的最后一节 该提案旨在测试细胞周期的功能重要性 V-Abl和bcr-1对细胞周期的调控作用 ABL.我们将检验一种假设，即细胞周期调节受损 使其更容易发生Abelson转换，即PRO/Preb细胞 V-abl变换的偏好可以部分地由方面决定 细胞周期调控和v-Abl转化株可能含有 其产物调节细胞周期的基因突变。

We have shown that v-Abl initiates a signal transduction which leads to activation of Ras, Raf and cyclin dependent kinases (Cdks) with subsequent hyperphosphorylation of Rb family proteins, activation of E2F/DP proteins and induced transcription of E2F-dependent genes including c-myc and DHFR. Since our results show that v-Abl has direct effects on cell cycle, it is important to characterize fully how v-Abl and BCR-ABL affect cell cycle and to assess the importance of cell cycle regulation for Abl-dependent transformation. Cell cycle regulation is central to growth regulation and therefore understanding these mechanisms is critical to understanding molecular mechanisms of Abelson transformation. In the first Specific Aim, fibroblast and preB cells transformed with a temperature sensitive form of v-Abl will be analyzed to determine how v- Abl will be analyzed to determine how v-Abl affects cell cycle regulation. Three important aspects of cell cycle regulation will be studied: 1) the cellular concentration of cyclins and Cdk inhibitors, 2) Cdk2 and Cdk4 activity and 3) induction of E2F- and c-Myc-dependent mRNAs. In Specific Aim II, we will test the hypothesis that v-Abl signaling which depends upon Abi-l or Jaks affects cell cycle regulation. Cell lines generated by the Goff and Rothman groups which have detected signaling by Abi-l or Jaks will be compared to normal cells for v-Abl-dependent cell cycle regulation. In Specific Aim II the ability of BCR-ABL to affect cell cycle will be studied by analyzing primary samples samples from CML patients and by studying cell lines transformed with temperature sensitive bcr-abl. The last section of the proposal is designed to test the functional importance of cell cycle regulation of cell cycle regulation for transformation by V-Abl and BCR- ABL. We will test the hypothesis that impaired cell cycle regulation makes more susceptible to Abelson transformation, that the pro/preB cell preference of v-Abl transformation may be determined in part by aspects of cell cycle regulation and that v-Abl transformed lines may harbor mutations in genes whose products regulate cell cycle.