Mechanisms of switching on p53: a role for covalent modification?

Abstract

The p53 protein plays a pivotal role in activating and integrating adaptive cellular responses to a wide range of environmental stresses. Activation of p53 can occur by di erent molecular routes, depending on the nature of the activating signal. Central to the activation process, by whichever route, is the destabilization of the p53-MDM2 interaction. The molecular mechanisms which activate p53 involve elements of post-translational modi®cation, protein stabilization and protein-protein interaction. Two central themes are emerging from recent work in this area. The ®rst is that there are common events in the p53 activation process among di erent activating pathways. The second is that activation involves not just a single molecular event such as disruption of the p53-MDM2 interaction, but a series of sequential events the nature of which is governed by the type of activating stimulus. This review summarizes our current knowledge of the p53 activation process in response to two stimuli, DNA damage and activated oncogenes, and considers the contribution made by multisite phosphorylation in determining the nature of the p53 response.

Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells

“…Together, these results suggest a feed-forward loop between the production of ROS, the stabilization of p53 protein and the consequent induction of apoptosis. Though the physiologic stimulant of p53 stabilization remains to be defined 33 , we hypothesize that one important stimulant involves ROS and that a primary evolutionary function of p53 will be to protect cells from the effects of oxidative stress. At the animal level, this idea can be tested in mice, Drosophila and Caenorhabditis elegans with disruptions of their ferredoxin reductase homologs.…”

MicroRNA Responses to Cellular Stress

“…Therefore, these cells react to the stress (administered in this fashion) through a significant transcriptional response; however, our results show that ionizing radiation, which directly damages DNA, does not change the miRNA expression profile. Hence, the DNA damage response (i.e., DNA repair, cell cycle arrest, and/or apoptosis) is not likely to be mediated by miRNAdependent events, but rather occurs at the level of protein stability (35) and/or transcriptional activation (36). Our data suggest that the toxins that act via alterations in miRNA expression are primarily those associated with nongenotoxic or epigenetic modes of action.…”

Activation and activities of the p53 tumour suppressor protein

“…Numerous phosphorylation sites within or near the N-terminal MDM2-binding region of p53 have been described (Meek, 1999;Ljungman, 2000) and phosphorylation at many of these sites can attenuate binding of p53 to MDM2 in vitro, potentially leading to stabilization of p53 in vivo (Unger et al, 1999;Chehab et al, 2000;Sakaguchi et al, 2000;Shieh et al, 1997Shieh et al, , 2000. The kinases signalling to p53 include casein kinase 1 and 2, ATM (ataxia telangiectasia mutated), ATR (ATM/Rad3 related kinase) CHK1 and 2, JNK (jun N-terminal kinase) and DNA-PK (DNA-dependent protein kinase) (Jayaraman and Prives, 1999).…”