P53 in blind subterranean mole rats - Loss-of-function versus gain-of-function activities on newly cloned Spalax target genes

A. Avivi*, O. Ashur-Fabian, A. Joel, L. Trakhtenbrot, K. Adamsky, I. Goldstein, N. Amariglio, G. Rechavi, E. Nevo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

A tumor suppressor gene, p53, controls cellular responses to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Recently, we demonstrated that in blind subterranean mole rats, Spalax, a model organism for hypoxia tolerance, the p53 DNA-binding domain contains a specific Arg174Lys amino acid substitution. This substitution reduces the p53 effect on the transcription of apoptosis genes (apaf1, puma, pten and noxa) and enhances it on human cell cycle arrest and p53 stabilization/homeostasis genes (mdm2, pten, p21 and cycG). In the current study, we cloned Spalax apaf1 promoter and mdm2 intronic regions containing consensus p53-responsive elements. We compared the Spalax-responsive elements to those of human, mouse and rat and investigated the transcriptional activity of Spalax and human Arg174Lys-mutated p53 on target genes of both species. Spalax and human-mutated p53 lost induction of apaf1 transcription, and increased induction of mdm2 transcription. We conclude that Spalax evolved hypoxia-adaptive mechanisms, analogous to the alterations acquired by cancer cells during tumor development, with a bias against apoptosis while favoring cell arrest and DNA repair.

Original languageEnglish
Pages (from-to)2507-2512
Number of pages6
JournalOncogene
Volume26
Issue number17
DOIs
StatePublished - 12 Apr 2007

Funding

FundersFunder number
Ancell Teicher Research Foundation for Genetics and Molecular Evolution

    Keywords

    • Hypoxia
    • Subterranean mole rat
    • apaf1
    • mdm2
    • p53

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