Control of Reversible Growth Arrest and Survival by the C/EBP Family of Transcription Factors

当细胞退出细胞周期并进入可逆的生长停滞状态（称为G 0或静止）时激活的信号通路仍然知之甚少。 在过去的18个月里，我们已经确定，低氧水平（缺氧）提供的信号诱导生长停滞特定（气体基因）在静止的鸡胚成纤维细胞（CEF）。 以p20 K脂质运载蛋白基因作为gas基因的模型，我们鉴定了CHOP-C/EBP 3转录因子作为一种新的低氧应答因子，控制静止期CEF中gas基因的表达。 C/EBP 3是转录因子“碱性区和亮氨酸拉链”（bzip）家族的成员，其作为二聚体起调节能量代谢、免疫应答和多种组织的分化的作用。 在这些过程中，C/EBP 3通常起着矛盾的作用，增强细胞存活或使细胞死亡，促进细胞分化或有利于细胞增殖。 C/EBP的多效性作用的分子机制仅部分被理解，但取决于其与C/EBP家族的其他成员（如CHOP）以及与无关的转录因子的相互作用。 该提案的工作假设是：C/EBP 3在可逆生长停滞期间作为控制基因表达和细胞命运的“开关”因子发挥作用。提出的研究的中心目标是确定C/EBP 3在控制细胞命运中的多效性作用的机制。 可逆的生长停滞在发育、组织再生和诸如癌症的病理学的若干过程中是至关重要的。 因此，控制可逆生长停滞的机制的表征将提高我们对影响加拿大人福祉的过程的理解，特别是随着人口老龄化。

Signaling pathways activated when cells exit the cell cycle and enter a state of reversible growth arrest, known as G0 or quiescence, remain poorly understood. In the last eighteen months, we have determined that low oxygen levels (hypoxia) provide the signal for the induction of growth-arrest specific (gas genes) in quiescent chicken embryo fibroblasts (CEF). Using the p20K lipocalin gene as a model of gas gene, we identified the CHOP-C/EBPß transcription factor as a novel hypoxia-responsive factor controlling the expression of gas genes in quiescent CEF. C/EBPß is a member of the "basic region & leucine zipper" (bzip) family of transcription factors functioning as dimers to regulate energy metabolism, the immune response and the differentiation of several tissues. In these processes, C/EBPß often plays paradoxical roles, enhancing cell survival or enabling cell death, promoting cell differentiation or favoring cell proliferation. The molecular mechanisms underlying this pleiotropic action of C/EBPß are only partly understood but depend on its interaction with other members of the C/EBP family, like CHOP, and with unrelated transcription factors. The working hypothesis of the proposal is that: C/EBPß functions as a "switch" factor controlling gene expression and cell fate during reversible growth arrest". The central objective of the proposed studies is to define the mechanisms underlying the pleiotropic action of C/EBPß in the control of cell fate. Reversible growth arrest is paramount in several processes of development, tissue regeneration and in pathologies such as cancer. Therefore, the characterization of the mechanisms controlling reversible growth arrest will improve our understanding of processes affecting the well being of Canadians, particularly as the population is aging.