The Δ133p53 isoform and its mouse analogue Δ122p53 promote invasion and metastasis involving pro-inflammatory molecules interleukin-6 and CCL2

Abstract

A number of naturally occurring isoforms of the tumour suppressor protein p53 have been discovered, which appear to have differing roles in tumour prevention or promotion. We are investigating the tumour-promoting activities of the Δ133p53 isoform using our mouse model of Δ133p53 (Δ122p53). Here, we report that tumours from Δ122p53 homozygous mice show evidence of invasion and metastasis and that Δ122p53 promotes migration though a 3-dimensional collagen matrix. We also show that Δ122p53 and Δ133p53 promote cell migration in scratch wound and Transwell assays, similar to the 'gain-of-function' phenotypes seen with mutant p53. Using the well-defined B16 mouse melanoma metastatic model, we show that Δ122p53 leads to faster generation of lung metastases. The increased migratory phenotypes are dependent on secreted factors, including the cytokine interleukin-6 and the chemokine CCL2. We propose that Δ122p53 (and Δ133p53) acts in a similar manner to 'gain-of-function' mutant p53 proteins to promote migration, invasion and metastasis, which may contribute to poor survival in patients with Δ133p53-expressing tumours.

p53 targets TSPAN8 to prevent invasion in melanoma cells

“…33 Very recently, Roth et al showed that the mouse-specific isoform Δ122p53, similar to the human Δ133p53 isoform, which is overexpressed in melanoma, 34 promoted invasion in an IL-6- and CCL2-dependent manner. 35 We therefore tested whether p53 could specifically regulate invasion in a Tspan8-dependent manner. p53 silencing was shown to increase the invasiveness of T1C3 melanoma cells in Boyden chambers (Figure 4a), whereas p53 stabilization by nutlin-3 treatment is sufficient to decrease invasive capacities (Figure 4b).…”

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

“…D133p53a has been shown to stimulate proliferation (6) and angiogenesis of tumor cells (6) and D133p53b promotes stem cell differentiation by upregulating pluripotency factors such as SOX2, OCT3/4, and NANOG (24). A mouse model of D133p53 designated D122p53 was shown to promote hyperproliferation, tumorigenesis, and inflammation (9) and overexpression of D122p53 promoted cell migration, invasion through three-dimensional (3D) matrices (16), and upregulation of metastasis-associated proteins (14). Finally, recent data from the D122p53 mouse has shown that there is also cooperativity as D122p53 enhanced the survival of p53-mutant mice (25) and full-length p53 increased the ability of D122p53 to promote cell migration (16).…”

“…A mouse model of D133p53 designated D122p53 was shown to promote hyperproliferation, tumorigenesis, and inflammation (9) and overexpression of D122p53 promoted cell migration, invasion through three-dimensional (3D) matrices (16), and upregulation of metastasis-associated proteins (14). Finally, recent data from the D122p53 mouse has shown that there is also cooperativity as D122p53 enhanced the survival of p53-mutant mice (25) and full-length p53 increased the ability of D122p53 to promote cell migration (16). This is consistent with the isoforms functioning in a complex network to determine cell fate outcomes (17).…”

“…Multiple studies have now shown that p53 isoforms have distinct functions and frequently contribute to diseases including cancer (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Elevated expression of the D40p53 isoform has been associated with metastatic melanoma and triple-negative breast cancers (7,19).…”

Conformational stability and dynamics of the cancer‐associated isoform Δ133p53β are modulated by p53 peptides and p53‐specific DNA

“…D133p53b also prevents cancer cells from undergoing apoptosis in a RhoB-dependent manner (40). It has been suggested that the D133p53 isoform and its mouse analog D122p53 promote invasion and metastasis in a manner similar to gain-offunction of mutant p53 proteins (41). Therefore, it is important to understand the physicochemical properties of D133p53b compared with p53 protein with normal DBD.…”