Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice.

Amanda M Goh,Poh Cheang Chiam,Karen M Mann,Julin S Wong,David P Lane,Marc Leushacke,Siti Aishah Binte Rahmat,Michael B Mann,Ling Li,Nick Barker,Tamara Terzian,Guillermina Lozano,Yuezhen Xue

doi:10.18632/oncotarget.4956

Abstract

The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High levels of mutant p53 can be found in tumours and the accumulation of mutant p53 has previously been reported in pathologically normal cells in human skin. We show for the first time that similarly elevated levels of mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model. In fact, in the small intestine, mutant p53 spontaneously accumulates in a manner dependent on gene dosage and cell type. Mutant p53 protein is regulated similarly to wild type p53, which can accumulate rapidly after induction by ionising radiation or Mdm2 inhibitors, however, the clearance of mutant p53 protein is much slower than wild type p53. The accumulation of the protein in the murine small intestine is limited to the cycling, crypt base columnar cells and proliferative zone and is lost as the cells differentiate and exit the cell cycle. Loss of Mdm2 results in even higher levels of p53 expression but p53 is still restricted to proliferating cells in the small intestine. Therefore, the small intestine of these p53 mutant mice is an experimental system in which we can dissect the molecular pathways leading to p53 accumulation, which has important implications for cancer prevention and therapy.

Highlights

The p53 tumour suppressor protein is a transcription factor that activates genes responsible for acute radiationinduced death, cell cycle checkpoint function, induction of apoptosis and senescence and tumour suppression
We show that mutant p53 protein is detectably expressed in a specific cell population of morphologically normal small intestine and in other tissues in both absence and presence of p53-activating signals and even in the presence of active Mdm2
R172H mutant p53 protein levels may be elevated in preneoplastic cells, we examined morphologically normal tissues in the p53R172H/R172H mice to study the expression of mutp53

Summary

Introduction

The p53 tumour suppressor protein is a transcription factor that activates genes responsible for acute radiationinduced death, cell cycle checkpoint function, induction of apoptosis and senescence and tumour suppression. The p53 protein is essential for the regulation of cell proliferation, and mutant p53 over-expression is usually seen in malignant tumours. The missense mutant protein accumulates to high levels and extensive www.impactjournals.com/oncotarget immunohistochemical studies have shown that this accumulation is highly variable and that mutation alone is not sufficient to drive accumulation in all cells in the tumour leading to complex and variable staining patterns [7]. Mutation of the p53 gene results in loss of its tumour suppressive transcriptional activation properties and gain of novel oncogenic functions that are dependent on high level expression [8]. Genetic and xenograft data from mouse models have shown that the restoration of wild type p53 activity is a potential anticancer strategy [11,12,13,14,15,16]

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