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The effect of Δ122p53, a Δ133p53α-like isoform, on global gene expression in response to DNA damage in mouse splenocytes

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 Δ133p53α isoform is generated from an alternative transcription initiation site in intron 4 of the p53 gene (TP53) and lacks the N-terminus. Elevated expression of Δ133p53α has been observed in a variety of tumors. To explore the functions of Δ133p53α, we created a mouse expressing an N-terminal deletion mutant of p53 (Δ122p53) that corresponds to Δ133p53α. Δ122p53 mice show decreased survival and a different and more aggressive tumor spectrum compared to 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 pro-inflammatory phenotype having increased serum concentrations of interleukin (IL)-6 and other pro-inflammatory cytokines and lymphocyte aggregates in the lung and liver as well as other pathologies. Based on these observations, we propose that human Δ133p53α also functions to promote cell proliferation and inflammation, one or both of which contribute to tumor development. Total RNA was isolated from pooled splenocytes from four 5-6 week old mice with different p53 status (wild type, p53-/-, or Δ122p53) subjected to DNA damaging or control treatments.

ORGANISM(S): Mus musculus

SUBMITTER: Aaron Jeffs

PROVIDER: E-GEOD-27586 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The effect of Δ122p53, a Δ133p53α-like isoform, on global gene expression in response to DNA damage in mouse splenocytes

Project description: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 Δ133p53α isoform is generated from an alternative transcription initiation site in intron 4 of the p53 gene (TP53) and lacks the N-terminus. Elevated expression of Δ133p53α has been observed in a variety of tumors. To explore the functions of Δ133p53α, we created a mouse expressing an N-terminal deletion mutant of p53 (Δ122p53) that corresponds to Δ133p53α. Δ122p53 mice show decreased survival and a different and more aggressive tumor spectrum compared to 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 pro-inflammatory phenotype having increased serum concentrations of interleukin (IL)-6 and other pro-inflammatory cytokines and lymphocyte aggregates in the lung and liver as well as other pathologies. Based on these observations, we propose that human Δ133p53α also functions to promote cell proliferation and inflammation, one or both of which contribute to tumor development.

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