Hyperproliferation, cancer, and inflammation in mice expressing a Δ133p53-like isoform

Abstract

The p53 protein is a pivotal tumor suppressor that is frequently mutated in many human cancers, although precisely how p53 prevents tumors is still unclear. To add to its complexity, several isoforms of human p53 have now been reported. The ⌬133p53 isoform is generated from an alternative transcription initiation site in intron 4 of the p53 gene (Tp53) and lacks the N-terminus. Elevated levels of ⌬133p53 have been observed in a variety of tumors. To explore the functions of ⌬133p53, we created a mouse expressing an N-terminal deletion mutant of p53 (⌬122p53) that corresponds to ⌬133p53. ⌬122p53 mice show decreased survival and a different and more aggressive tumor spectrum compared with p53 null mice, implying that ⌬122p53 is a dominant oncogene. Consistent with this, ⌬122p53 also confers a marked proliferative advantage on cells and reduced apoptosis. In addition to tumor development, ⌬122p53 mice show a profound proinflammatory phenotype having increased serum concentrations of interleukin-6 and other proinflammatory cytokines and lymphocyte aggregates in the lung and liver as well as other pathologies. Based on these observations, we propose that human ⌬133p53 also functions to promote cell proliferation and inflammation, one or both of which contribute to tumor development. (Blood. 2011;117(19): 5166-5177) Introduction p53 is most important for preventing cancers. We know this because mice deleted for the p53 gene (Trp53) are highly tumor prone 1 ; in humans, Li-Fraumeni syndrome, characterized by multiple tumor phenotypes, is the result of germline inherited mutations in the p53 gene (Tp53) 2 ; and most common human cancers contain mutations in Tp53 (www.p53.iarc.fr), generally rendering the protein functionally impaired. Ten isoforms of human p53 have been reported that are generated by the use of alternative translation initiation sites, splicing, or alternative promoters. [3][4][5][6][7][8][9] Two p53 isoforms (⌬40p53 and ⌬133p53) lack the N-terminus of p53, whereas 4 others (⌬40p53␤, ⌬40p53␥, ⌬133p53␤, and ⌬133p53␥) also lack part of the C-terminus beyond codon 331. In addition, 3 more isoforms have recently been described (⌬160p53, ⌬160p53␤, ⌬160p53␥) that use an alternative start codon at position 161 in the transcript for the ⌬133p53 isoform family. 8 The isoforms are generally expressed in a variable and to some extent tissue specific manner, although the ⌬133p53 isoform appears to be ubiquitous. 5 Aberrant expression of the ⌬133p53 isoforms occurs in a variety of tumors, including breast, 5 head and neck, 10 acute myeloid leukemia, 11 melanoma, 12 colon cancer, 13 and ovarian cancer, 14 suggesting that ⌬133p53 contributes to tumor formation. In zebrafish, the homolog of ⌬133p53 (⌬113p53) attenuates p53-dependent apoptosis by activating the homolog (bcl2l) of the antiapoptotic protein Bcl-xl, 15 and knockdown of ⌬113p53 using silencing RNA induced p53-dependent apoptosis. In another study, overexpression of ⌬133p53 extended the life span of normal human fibroblasts by inhibiting replicative senescen...

Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

“…The latter group, represented by a human Δ133p53 isoform, has been suggested to promote tumorigenesis. This is consistent with a recent finding of strong spontaneous tumorigenesis in mice expressing the Δ122p53 protein that mimics the human Δ133p53 isoform (9). In human colon adenomas, the Δ133p53 isoform has been found to inhibit p53-mediated replicative senescence, and its increase may signal an escape from the senescence barrier during the progression from adenoma to carcinoma (10).…”

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

“…This complex expression pattern implies that sequences located in TP53 introns and involved in the production of alternative forms of the protein may have a critical impact on overall biological functions of p53 and may therefore be important target regions for somatic or germline variants. Mouse models have shown that constitutive expression of a short p53 isoform lacking the transactivation domain (D122p53) leads to chronic inflammation and a different and more aggressive tumor spectrum compared with TP53-null mice, suggesting that this isoform could act as a dominant oncogene (70).…”

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

“…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).…”

“…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).…”