Deconstructing networks of p53-mediated tumor suppression in vivo

Abstract

The transcription factor p53 is a vital tumor suppressor. Upon activation by diverse stresses including oncogene activation, DNA damage, hypoxia and nutrient deprivation, p53 activates a panoply of target genes and orchestrates numerous downstream responses that suppress tumorigenesis. Although early studies of p53 suggested that its ability to induce cell cycle arrest, senescence and apoptosis programs accounted for its tumor-suppressor activity, more recent studies have challenged this notion. Moreover, p53 regulates a suite of additional processes, such as metabolism, stem cell function, invasion and metastasis. The processes p53 coordinately regulates to enact tumor suppression, and how such regulation occurs, thus remain elusive. In this review, we will summarize our current knowledge of p53-mediated tumor-suppressive mechanisms gleaned from in vivo studies in mouse models.

Figure 1

p53 mutant mouse models. (a) Domain structure of p53. The arrowheads depict the location of mutations introduced into knock-in mouse models discussed in this review. PRD, proline-rich domain. Basic, basic amino-acid-rich region. (b) Descriptions of the mouse models with mutated forms of p53 discussed in this review

Figure 2

p53-activating stresses and responses. (a) The classical view of p53 can induce and response. In response to acute DNA damage, p53 can induce apoptosis, cell cycle arrest and senescence. These responses are dispensable for the suppression of numerous diverse tumor types. (b) A revised view of p53 activation and response during tumor development. A suite of stresses in the context of a developing tumor can activate p53. These stresses may be cell intrinsic or cell extrinsic. Cell-intrinsic stresses include hyperproliferative signals and chronic DNA damage arising from events such as replication stress, telomere attrition and oxidative stress. Cell-extrinsic stresses, denoted by italics, include signals from the tumor microenvironment (TME), such as poor oxygen and nutrient availability. In addition, p53 may be active in the ‘basal’ state to maintain homeostasis. Upon activation, p53 can function in numerous cellular pathways to oppose tumorigenesis. Which functions are activated by a given stress and contribute to tumor suppression is still under investigation

Figure 3

p53 suppresses cancer development through transcriptional regulation of target genes that regulate diverse cellular processes. p53 has been proposed to regulate a plethora of functions including apoptosis, cell cycle arrest, senescence, DNA repair, ferroptosis, metabolism, autophagy, stem cell function, invasion and metastasis. In addition, p53 is proposed to have non-cell autonomous functions that allow communication within the tumor microenvironemt (TME). Multiple target genes have been implicated in each response, and those that are activated by p53 are indicated in black. Of note, p53 has also been suggested to act as a transcriptional repressor. Select genes to which p53 binds and represses transcription are indicated in red. The murine gene annotation is shown unless the gene has no mouse ortholog

Figure 4

Diverse p53-regulated processes lead to common outcomes. Although p53 regulates many cellular processes (top), they all likely impinge upon the common outcomes of limiting cellular proliferation, through effects on both cell survival and cell division, and maintaining homeostasis. Regulating proliferation and promoting cellular homeostasis can lead to tumor suppression. Multiple p53 functions can potentially contribute to each of these tumor-suppressive outcomes, as indicated by arrows