Role of C/EBP in Cell Survival and Neoplasia

描述（由申请人提供）：最近的研究已经确定了碱性亮氨酸拉链转录因子CCAAT/增强子结合蛋白-β（C/EBPb）在细胞存活和肿瘤发展中的新功能作用;然而，对C/EBPb调节这些过程的分子机制知之甚少。C/EBPb-/-小鼠对致癌物诱导的皮肤肿瘤发展是完全难治的，所述致癌物产生具有致癌Ras突变的肿瘤。响应于局部致癌物治疗，与野生型小鼠相比，C/EBPb-/-小鼠显示角质形成细胞凋亡增加17倍。C/EBPb-/-小鼠细胞凋亡的异常增加需要p53，这是由于p53蛋白的异常上调。我们假设C/EBPb通过抑制p53介导了启动的肿瘤前体细胞的存活，并且C/EBPb缺乏的后果是p53的去抑制、p53介导的肿瘤前体细胞凋亡和肿瘤发生的消融。了解C/EBPb-/-小鼠中的促凋亡反应对肿瘤的发展具有重要意义。确切地说，C/EBPb如何抑制p53水平，以及这种抑制是否在DNA损伤和/或Ras诱导的致癌应激反应中发生尚不清楚。如果C/EBPb对致癌Ras肿瘤细胞的存活至关重要，那么在p53-proficient致癌Ras含有肿瘤中阻断C/EBPb功能应导致肿瘤细胞凋亡和肿瘤消退，因此我们建议C/EBPb具有作为癌症治疗的分子靶点的潜力。本研究的目的是：1）确定C/EBPb如何抑制p53/凋亡，并确定这种抑制是否响应于DNA损伤和/或致癌Ras而发生; 2）确定C/EBPb对p53的抑制是否是肿瘤发生的关键; 3）确定Ras和/或DNA损伤诱导的C/EBPb翻译后修饰在体内的重要性;以及4）确定C/EBPb是否是肿瘤消退的潜在分子靶点。该提案的长期目标是了解C/EBPb影响上皮中的肿瘤过程并调节肿瘤细胞存活的分子机制。

DESCRIPTION (provided by applicant): Recent studies have identified novel functional roles for the basic leucine zipper transcription factor CCAAT/enhancer binding protein-beta (C/EBPb) in cell survival and tumor development; however, the molecular mechanisms through which C/EBPb regulates these processes are poorly understood. C/EBPb-/- mice are completely refractory to skin tumor development induced by carcinogens that produce tumors with oncogenic Ras mutations. In response to topical carcinogen treatment, C/EBPb-/- mice display a 17-fold increase in keratinocyte apoptosis compared to wild type mice. This abnormal increase in apoptosis in C/EBPb-/- mice requires p53 and is due to aberrant up-regulation of p53 protein. We hypothesize that C/EBPb mediates the survival of initiated tumor precursor cells through the repression of p53 and that the consequences of C/EBPb deficiency are de-repression of p53, p53-mediated tumor precursor cell apoptosis and ablation of tumorigenesis. Understanding the pro-apoptotic response in C/EBPb-/- mice has important implications for tumor development. Exactly how C/EBPb represses p53 levels and whether this repression occurs in response to DNA damage and/or Ras-induced oncogenic stress is not known. If C/EBPb is critical for oncogenic Ras tumor cell survival then blocking C/EBPb function in a p53-proficient oncogenic Ras-containing tumor should result in tumor cell apoptosis and tumor regression, thus we propose that C/EBPb has potential as a molecular target for cancer therapy. The goals of this proposal are: 1) to determine how C/EBPb represses p53/apoptosis and determine whether this repression occurs in response to DNA damage and/or oncogenic Ras; 2) to determine whether repression of p53 by C/EBPb is critical for tumorigenesis; 3) determine the importance of Ras and/or DNA damage-induced C/EBPb post-translation modifications in vivo; and 4) to determine whether C/EBPb is a potential molecular target for tumor regression. The long-term objectives of this proposal are to understand the molecular mechanisms through which C/EBPb influences the neoplastic process in epithelia and regulates tumor cell survival.