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

我们已经表明，v-Abl启动了一个信号转导，导致 Ras、Raf和细胞周期蛋白依赖性激酶（Cdks）的活化， 随后Rb家族蛋白的过度磷酸化， E2 F/DP蛋白和E2 F依赖性基因的诱导转录 包括c-myc和DHFR。由于我们的结果表明，v-Abl具有直接 对于细胞周期的影响，重要的是要充分表征v-Abl 和BCR-ABL对细胞周期的影响，并评估细胞周期的重要性 调节依赖于细胞的转化。细胞周期调控是 对生长调节至关重要， 机制对于理解Abelson的分子机制至关重要 转型 在第一个特定目标中，成纤维细胞和前B细胞转化了一个 将分析v-Abl温度敏感形式，以确定v-Abl 将分析Abl以确定v-Abl如何影响细胞周期 调控细胞周期调控的三个重要方面将是 研究：1）细胞周期蛋白和Cdk抑制剂的细胞浓度， 2)Cdk 2和Cdk 4活性和3）E2 F-和c-Myc-依赖性的诱导 mRNA。在具体目标II中，我们将检验v-Abl 依赖于Abi-1或Jaks的信号传导影响细胞周期 调控由Goff和Rothman小组产生的细胞系， 已经检测到Abi-I或Jaks的信号传导的人将与正常人进行比较， v-Abl依赖的细胞周期调节。在《具体目标II》中， 通过分析BCR-ABL影响细胞周期的能力， 通过研究细胞系， 用温度敏感的bcr-abl转化。 一项旨在测试细胞周期功能重要性的提案 通过V-Abl和BCR调节转化的细胞周期调节， 消融导管我们将检验细胞周期调节受损 使其更容易发生Abelson转化， v-Abl转化的偏好可以部分地由以下方面确定 细胞周期调控的作用，并且v-Abl转化的细胞系可能具有 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.