Cytoplasmic functions of the tumour suppressor p53

Abstract

The principal tumour-suppressor protein, p53, accumulates in cells in response to DNA damage, oncogene activation and other stresses. It acts as a nuclear transcription factor that transactivates genes involved in apoptosis, cell cycle regulation and numerous other processes. An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy. These previously unknown functions contribute to the mission of p53 as a tumour suppressor.

Fig. 1

Classification of p53 activities. On the left side, some genes that are transactivated by p53 are exemplified, together with a few of the functional consequences of p53 activation. On the right side, transactivation-independent effects of p53 are listed. These can be divided into nuclear and extranuclear (cytoplasmic) p53 activities.

Fig. 2

Interplay of the nuclear and cytoplasmic functions of p53 in apoptosis. Nuclear p53 induces the expression of MDM2, which acts to inhibit the protein through binding and ubiquitinylation. Cellular stress signals interrupt this inhibition, allowing p53 to accumulate both in the nucleus and in the cytoplasm. In the latter, p53 is sequestered by anti-apoptotic Bcl-2 proteins such as Bcl-X_L. Another target of nuclear p53, PUMA, functions to disrupt the Bcl-X_L-p53 interaction. The released p53 can now trigger MOMP and apoptosis through interaction with, for example, Bax.

Fig. 3

Concerted oncogenic actions of mutant p53 (a) or inactive ARF (b) in the nucleus and cytoplasm of cancer cells. Hot spot mutations of p53 affecting the DNA binding domain can abolish the transactivation of p53 genes as well as the mitochondrion-permeabilizing action of p53, yet leave intact autophagy inhibition by p53 (a). Similarly, oncogenic mutations that affect the C-terminus of ARF can lead to the depletion of p53 protein, as well as to the abolition of mitochondrion-permeabilizing and autophagy-inducing activities mediated by the ARF protein (b).