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

Tania L Slatter,Noelyn Hung,Hamish Campbell,Carina Rubio,Reena Mehta,Prudence Renshaw,Gail Williams,Michelle Wilson,Afra Engelmann,Aaron Jeffs,Janice A Royds,Margaret A Baird,Antony W Braithwaite

doi:10.1182/blood-2010-11-321851

Tania L Slatter, Noelyn Hung + Show 11 more

Open Access

https://doi.org/10.1182/blood-2010-11-321851

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Journal: Blood	Publication Date: May 12, 2011
Citations: 61	License type: cc-by

Affiliation: University of Otago, University of Sydney

Abstract

AbstractThe 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 Δ133p53 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 Δ133p53 have been observed in a variety of tumors. To explore the functions of Δ133p53, we created a mouse expressing an N-terminal deletion mutant of p53 (Δ122p53) that corresponds to Δ133p53. Δ122p53 mice show decreased survival and a different and more aggressive tumor spectrum compared with p53 null mice, implying that Δ122p53 is a dominant oncogene. Consistent with this, Δ122p53 also confers a marked proliferative advantage on cells and reduced apoptosis. In addition to tumor development, Δ122p53 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 Δ133p53 also functions to promote cell proliferation and inflammation, one or both of which contribute to tumor development.

Highlights

P53 is most important for preventing cancers
Overexpression of ⌬133p53 extended the life span of normal human fibroblasts by inhibiting replicative senescence induced by the p53␤ isoform,[13] and a recent report showed that up-regulation of ⌬133p53 in cell culture inhibits apoptosis and G1 arrest induction mediated by full-length p53 but does not affect induction of G2 arrest.[16]
We argue that human ⌬133p53 has similar functions and is an oncogene

Summary

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. 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, 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. We argue that human ⌬133p53 has similar functions and is an oncogene

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