p53: More than a Transcription Factor?

The p53 tumor suppressor protein is widely known for its role as a transcription factor that regulates the expression of stress response genes and mediates a variety of anti-proliferative processes.1 Underscoring its importance in the regulation of proliferative homeostasis, it is the most commonly mutated tumor suppressor in human cancers.2 It is known to mediate its effects through the activation of genes regulating cell cycle checkpoints, DNA damage and repair, and apoptosis.1 For apoptosis specifically, p53 enhances the expression of Bcl-2 family members including Bax, BID, PUMA, and Noxa.3-6 It is also known to regulate APAF-1, a co-activator of the apoptosis initiator Caspase-9.7 Although its role as a mediator of transcription is well established, some studies appear to suggest that p53 might affect apoptosis via novel transcription-independent pathways. For instance, apoptosis can still occur in the presence of inhibitors of protein synthesis, or when p53 mutants incapable of acting as transcription factors are ectopically expressed.8-11 In a new study, Chipuk et al. provide further evidence supporting the notion that p53 can act in a transcription-independent manner.12

Figure 1. p53-dependent apoptosis still occurs when either nuclear translocation is blocked with WGA, or protein synthesis is blocked by cycloheximide. Transcription-independent apoptosis pathways may include direct p53 effects on Bax, or p53-dependent release of BID from Bcl-xL sequestration.

Apoptosis still occurs in mouse embryonic fibroblasts (MEFs) treated with wheat germ agglutinin (WGA) to inhibit UV-induced p53 nuclear translocation and subsequently block transcription of several p53-responsive genes (MDM2, Bax, p21/CIP1/CDKNIA, and PUMA; Figure 1). In addition, p53 isolated from UV-treated MCF-7 cells (p53UVIP) and microinjected into HeLa cells at physiological concentrations, still stimulates Cytochrome c release even in the presence of WGA to prevent nuclear translocation, or cycloheximide to prevent new protein synthesis (Figure 1). This activity requires the accumulation of p53 in the cytoplasm, since a transcriptionally impaired mutant (p53QS) does not stimulate apoptosis unless blocked from nuclear translocation by WGA. The underlying mechanism appears to involve the pro-apoptotic Bcl-2 family member Bax. It was shown that Bax is required for Cytochrome c release by p53-treated mitochondria in vitro, and in the apoptosis of UV/WGA-treated MEFs. Moreover, p53 also causes Bax to form oligomers and release fluorescent dextrans from liposomes in in vitro assays designed to mimic mitochon-drial outer membrane permeablization. Part of this transcription-independent mechanism may also involve p53-induced release of bound pro-apoptotic Bax and/or Bid. p53 directly interacts with Bcl-xL, leading to the release of both Bax and Bid from Bcl-xL sequestration.

These results suggest that p53 can indeed act as more than just a tran-scription factor. Using combinations of pharmacological and genetic approaches, Chipuk et al. demonstrate that p53 triggers apoptosis pathways independent of measurable nuclear activity.12 Future studies will further investigate these alternative pathways, deciphering the circumstances under which they occur, and ultimately their physiological importance.


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