Mutant p53 in cell-cell interactions

Abstract

p53 is an important tumor suppressor, and the complexities of p53 function in regulating cancer cell behaviour are well established. Many cancers lose or express mutant forms of p53, with evidence that the type of alteration affecting p53 may differentially impact cancer development and progression. It is also clear that in addition to cell-autonomous functions, p53 status also affects the way cancer cells interact with each other. In this review, we briefly examine the impact of different p53 mutations and focus on how heterogeneity of p53 status can affect relationships between cells within a tumor.

Keywords: cancer; cell competition; cell-cell interactions; mutant p53.

Figure 1.

Acquisition and impact of mutant p53 status. Expression of a mutant p53 protein is associated with more aggressive behavior in many cancer types, and mutant p53 status may be acquired through several mechanisms. Following point mutation in TP53, cancer cells can become genetically homozygous or hemizygous through loss of the WT allele (loss of heterozygosity). However, in cells that retain WT p53, the dominant-negative activity of mutant p53 can inhibit the WT protein and render the cell functionally mutant for p53. Finally, the adoption of a pseudomutant p53 conformation by the WT protein can allow mutant p53 behavior in cells without a TP53 mutation. Additional gain-of-function activities of mutant p53, beyond loss of WT activities, are associated with progression to metastasis in several cancer types.

Figure 2.

Mechanisms of mutant p53 action. The acquisition of p53 mutation can lead to the formation of heterotetramers made up of WT and mutant monomers. The presence of mutant subunits in a tetramer can reduce WT p53 activity and, through this dominant-negative activity, allow for tumor development. However, many tumors lose the remaining wild-type allele, leading to the expression of only mutant protein. Mutant p53 is frequently stabilized in cancer cells, in part as a consequence of complex with chaperone proteins, allowing it to mediate a variety of new activities (gains of function) via a number of different mechanisms.

Figure 3.

A role for p53 in cell competition. (A) Several studies have shown that WT p53 is required in aberrant cells that are outcompeted by surrounding cells containing WT p53. Loss of p53 allows the expansion of the aberrant clone. (B) In other contexts, cells expressing mutant p53 protein are outcompeted by WT p53-expressing cells and eliminated from epithelial layers. A similar loser phenotype is displayed by mutant KRAS-expressing cells. However, in the context of a mutant KRAS-expressing epithelial layer, cells with a concurrent mutation in TP53 are not outcompeted.

Figure 4.

Heterogeneous p53 status in tumors. While some cancers retain a WT TP53 gene, mutations in TP53 occur during the development of many cancers, leading to expansion of clones of tumor cells that express no p53 or a mutant p53 protein among the WT p53-expressing cells. In some tumors, this heterogeneity of p53 expression persists, but most cancers tend to become clonal for cells carrying the TP53 mutation, leading to genetic homozygosity with respect to TP53. However, signals that drive WT p53 into a pseudomutant conformation, or changes in adhesion characteristics within the tumor that result in loss of mutant p53 protein expression, can result in heterogeneity in p53 expression within a tumor that is clonal for the TP53 gene.