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.
