Tumor-Suppressor Functions of the TP53 Pathway

Abstract

The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer development, whereas reinstatement of TP53 function results in regression of established tumors that had been initiated by loss of TP53. Remarkably, despite extensive investigation, the specific mechanisms by which TP53 acts as a tumor suppressor are yet to be fully defined. We review the history and current standing of efforts to understand these mechanisms and how they complement each other in tumor suppression.

Figure 1.

Appropriate activation and feedback control of TP53 activity is critical to effective tumor suppression. (A) In the absence of a TP53-activating signal, TP53 protein levels are maintained at low levels in most cell types by the E3 ubiquitin ligase, MDM2 (HDM2), which ubiquitinates (Ub) TP53 and targets it for degradation by the proteosome. (B) The TP53 protein may also control gene expression in the absence of an activating stimulus, for example, by transcriptional repression. The extent to which basal TP53 activities contribute to the tumor-suppressor function is not known. (C) Stress stimuli, such as oncogene expression, DNA damage, and metabolic dysfunction, rapidly lead to TP53 protein accumulation and activation; this is in part owing to inhibition of MDM2 (HDM2), thus preventing TP53 ubiquitination and proteosomal degradation. Following activation, the TP53 protein acts as a sequence-specific transcription factor directing the expression of a large number of target genes, which are considered the primary determinants of the tumor-suppressor response. The specific mode of the TP53 response is influenced by extensive posttranslational modification, including acetylation (Ac) and phosphorylation (P).

Figure 2.

The TP53 protein exerts its tumor-suppressor function as a sequence-specific transcription factor. Following activation, the TP53 protein directs the expression of a large number of genes encoding mRNA, miRNA, and lincRNAs that orchestrate a variety of cellular processes. In addition, TP53 may have as yet undetermined effector functions that are important for tumor suppression. It is increasingly apparent that a single effector function is inadequate to explain the potency and complexity of TP53’s tumor-suppressor function. In contrast, specific effector functions may be more or less important depending on the context and multiple effector pathways are likely to collaborate and synergize in the prevention and suppression of tumor formation. Selected TP53-regulated murine genes are shown with their associated cellular processes (some genes may impact on various pathways, e.g., CDKN1a [p21], which is critical for G₁ cell-cycle arrest and cell senescence).