How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?

Abstract

The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransformed cells to many anticancer therapeutics, particularly those that cause DNA damage. P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death. For a long time, induction of apoptotic death in nascent neoplastic cells was regarded as the principal mechanism by which p53 prevents tumour development. This concept has, however, recently been challenged by the findings that in striking contrast to Trp53-deficient mice, gene-targeted mice that lack the critical effectors of p53-induced apoptosis do not develop tumours spontaneously. Remarkably, even mice lacking all mediators critical for p53-induced apoptosis, G1/S boundary cell cycle arrest and cell senescence do not develop any tumours spontaneously. In this review we discuss current understanding of the mechanisms by which p53 induces cell death and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy.

Figure 1

Regulation of p53 protein level and activity in unstressed versus stressed cells. Models depicting the mechanisms that regulate p53 protein levels and activity in unstressed cells and in cells undergoing stress, for example, due to the activation of oncogenes or DNA lesions that they have sustained. (Ub, ubiquitin; P, phosphorylation; Ac, acetylation)

Figure 2

Mechanisms of p53-induced apoptosis. Model depicting the mechanism by which activated p53 induces apoptosis through the BCL-2-regulated pathway. Fat arrows indicate p53-induced targets that are essential for p53-induced apoptosis. Thin arrows indicate p53-induced targets that are constituents of the BCL-2-regulated apoptotic pathway but are still expressed at levels sufficient for apoptosis induction in the complete absence of p53; that is, their induction by p53 may make the pathway work more efficiently, but this induction is not a sine qua non for p53-induced apoptosis, at least in haematopoietic cells. The broken arrow indicates that p53 may also activate BIM expression indirectly. The possible scenario that activation of targets that are not constituents of the apoptosis machinery per se can impact on apoptosis indirectly is also depicted

Figure 3

P53 activates a multitude of cellular effector processes. Model showing a selected cellular effector processes that can be activated by p53. Some, but not all, of the p53 target genes that are critical for the execution of these processes are indicated. The challenge remains to understand of which of these processes are critical for tumour suppression in which setting; that is, cell of origin undergoing neoplastic transformation and nature of the oncogenic lesions driving their transformation

Figure 4

Impact of p53-induced apoptosis on tumour development. Models showing the impact of loss of p53-induced apoptosis on tumour development in different cancer models/settings

Figure 5

Impact of mutant p53 proteins on tumour development. Model depicting the mechanisms by which mutant p53 proteins, which are frequently highly overexpressed (compared with the wild-type p53 protein), on tumour development