At the Crossroads of Life and Death: The Proteins That Influence Cell Fate Decisions

SIMPLE SUMMARY: Cellular senescence and apoptosis were historically thought of as two distinct cell fate pathways. However, many of the proteins involved are integral to both pathways. In particular, the ability of p53 to regulate both senescence and apoptosis meant it was seen as the decisive factor in these decisions, yet questions remain about its ability to select on its own the most appropriate cell fate according to each situation. Therefore, cell fates are no longer considered fixed endpoints but dynamic states that can be shifted given the right combination of activation and/or inhibitions of cofactors. ABSTRACT: When a cell is damaged, it must decide how to respond. As a consequence of a variety of stresses, cells can induce well-regulated programmes such as senescence, a persistent proliferative arrest that limits their replication. Alternatively, regulated programmed cell death can be induced to remove the irreversibly damaged cells in a controlled manner. These programmes are mainly triggered and controlled by the tumour suppressor protein p53 and its complex network of effectors, but how it decides between these wildly different responses is not fully understood. This review focuses on the key proteins involved both in the regulation and induction of apoptosis and senescence to examine the key events that determine cell fate following damage. Furthermore, we examine how the regulation and activity of these proteins are altered during the progression of many chronic diseases, including cancer.