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

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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.