title: 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 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.
authors.affiliation: Department of Pathology, School of Medicine University of Otago, Dunedin, New Zealand.
authors.forename: Tania L
authors.initials: TL
authors.lastname: Slatter
authors.forename: Noelyn
authors.initials: N
authors.lastname: Hung
authors.forename: Hamish
authors.initials: H
authors.lastname: Campbell
authors.forename: Carina
authors.initials: C
authors.lastname: Rubio
authors.forename: Reena
authors.initials: R
authors.lastname: Mehta
authors.forename: Prudence
authors.initials: P
authors.lastname: Renshaw
authors.forename: Gail
authors.initials: G
authors.lastname: Williams
authors.forename: Michelle
authors.initials: M
authors.lastname: Wilson
authors.forename: Afra
authors.initials: A
authors.lastname: Engelmann
authors.forename: Aaron
authors.initials: A
authors.lastname: Jeffs
authors.forename: Janice A
authors.initials: JA
authors.lastname: Royds
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Baird
authors.forename: Antony W
authors.initials: AW
authors.lastname: Braithwaite
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53