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

当细胞退出细胞周期，进入可逆性生长停滞状态，即G0或静止状态时，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(低氧)为在静止的鸡胚胎成纤维细胞(CEF)中诱导生长停滞特异性基因(GAS基因)提供了信号。以p20K Lipocalin基因作为GAS基因的模型，我们鉴定了CHOP-C/EBP？转录因子是一个新的低氧反应因子，控制静止期CEF中GAS基因的表达。 C/EBP？是“基本区域和亮氨酸拉链”(BZIP)转录因子家族的成员，作为二聚体参与调节能量代谢、免疫反应和多种组织的分化。在这些过程中，C/EBP？经常扮演矛盾的角色，促进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？的这种多效性作用的分子机制仅被部分了解，但取决于它与C/EBP家族其他成员的相互作用，如CHOP，以及与无关转录因子的相互作用。 该方案的工作假设是：C/EBP？在可逆生长停滞期间作为“开关”因子控制基因表达和细胞命运。该研究的中心目标是确定C/EBP？在控制细胞命运中的多效性作用的机制。可逆生长停滞在发育、组织再生和癌症等病理过程中至关重要。因此，可逆生长停滞控制机制的特征将提高我们对影响加拿大人福祉的过程的理解，特别是在人口老龄化的情况下。

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.