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

• Published in: Blood Vol. 117; no. 19; pp. 5166 - 5177
• Main Authors: Slatter, Tania L., Hung, Noelyn, Campbell, Hamish, Rubio, Carina, Mehta, Reena, Renshaw, Prudence, Williams, Gail, Wilson, Michelle, Engelmann, Afra, Jeffs, Aaron, Royds, Janice A., Baird, Margaret A., Braithwaite, Antony W.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 12.05.2011; Americain Society of Hematology
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Blotting, Western; Cell Proliferation; Fluorescent Antibody Technique; Gene Expression; Gene Expression Profiling; Hematologic and hematopoietic diseases; Humans; Inflammation - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Neoplasms, Experimental - genetics; Oligonucleotide Array Sequence Analysis; Protein Isoforms - genetics; Reverse Transcriptase Polymerase Chain Reaction; Transduction, Genetic; Tumor Suppressor Protein p53 - genetics; Cell proliferation; Vertebrata; Molecular form; Mammalia; Hematology; Mouse; Animal; Rodentia; Inflammation; Malignant tumor; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-11-321851

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 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.