Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome

Abstract

Mutations in the TP53 gene commonly result in the expression of a full-length protein that drives cancer cell invasion and metastasis. Herein, we have deciphered the global landscape of transcriptional regulation by mutant p53 through the application of a panel of isogenic H1299 derivatives with inducible expression of several common cancer-associated p53 mutants. We found that the ability of mutant p53 to alter the transcriptional profile of cancer cells is remarkably conserved across different p53 mutants. The mutant p53 transcriptional landscape was nested within a small subset of wild-type p53 responsive genes, suggesting that the oncogenic properties of mutant p53 are conferred by retaining its ability to regulate a defined set of p53 target genes. These mutant p53 target genes were shown to converge upon a p63 signalling axis. Both mutant p53 and wild-type p63 were co-recruited to the promoters of these target genes, thus providing a molecular basis for their selective regulation by mutant p53. We demonstrate that mutant p53 manipulates the gene expression pattern of cancer cells to facilitate invasion through the release of a pro-invasive secretome into the tumor microenvironment. Collectively, this study provides mechanistic insight into the complex nature of transcriptional regulation by mutant p53 and implicates a role for tumor-derived p53 mutations in the manipulation of the cancer cell secretome.

p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3

“…23,24 The function of p53 as a master regulator in the cell cycle and its role in cancer development is well-documented. 25 It is speculated that TP53 is mutated in over half of all cancers, and that targeting of this molecule is important in the treatment of many cancer cell types. [26][27][28] Although the significance of p53 mutations in prostate cancer formation has been debated, recent studies have shown that deregulation of this protein appears to have a significant place in the advancement and metastatic potential of the disease.…”

Molecular dynamics of the full-length p53 monomer

“…117,118 This is, for example, evident in epidermis, 119 as well as in DNA damage response. 120 The p53 protein is highly conserved in its structure from C. elegans, D. melanogaster to H. sapiens. [121][122][123][124][125][126] While the DBD domain is highly conserved among vertebrates and invertebrates, the C terminus varies, resulting in a change from dimeric structure to a tetramer in the vertebrates.…”

The aggregation of mutant p53 produces prion-like properties in cancer

“…9 This co-aggregation occurs despite the existence of only 38% homology in the oligomerization domain of these proteins. 56 Nevertheless, the interaction between mutant p53 and p63 has been shown to be related to important gain-of-function effects in cancer that appear to be the result of either the enhanced expression of genes targeted by p63 57,58 or the binding of p63-p53 to unusual DNA sequences rather than to the loss of p63 DNA binding ability. 59 The existence of multiple isoforms of these three proteins further complicates these interactions and their effects, and the interactions between these proteins may lead to different cellular fates.…”