p21 Mediates Senescence by a Mechanism Involving Accumulation of Reactive Oxygen Species

Abstract

p21^{Waf1/Cip1/Sdi1} is a potent inhibitor of cyclin-dependent kinases (CDKs) and one of the best characterized p53 direct target genes. Moreover, it is one of the principal inducers of senescence, a permanent arrest phenotype related to ageing and the prevention of cell transformation. It was initially thought that p21 had tumour suppressor properties, due to its ability to stop cell cycle at different stages, either transitorily or permanently. However, recent evidence points to a much more complex picture. It is now well established that p21 itself can trigger apoptosis in certain situations, even independently of p53. On the other hand, p21-mediated cell arrest can actually limit the sensitivity to apoptotic stimuli. To complicate matters even further, p21 has been shown to have other direct pro-survival functions and could even be contributing to tumourigenesis through the secretion of growth factors by arrested cells. At the core of these antagonistic functions of p21 is the generation of Reactive Oxygen Species (ROS), which have been shown to be important both in the induction of apoptosis and the establishment of senescence, and could also participate in the negative effects on tissue homeostasis of the senescent cell secretome. p21 has the ability to stop cancer cell growth and is not mutated in cancer. However, without a better understanding of its pleiotropic functions we will not be able to harness its clinical potential. It is therefore important to investigate the mechanisms by which p21 affects cell physiology and its use of ROS as messengers and effectors.