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Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation.

ABSTRACT: The tumor suppressor gene p53 controls cellular response to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Inactivation of p53, found in 40-50% of human cancers, confers selective advantage under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its entire life cycle underground at decidedly lower oxygen tensions than any other mammal studied. Because a wide range of respiratory adaptations to hypoxic stress evolved in Spalax, we speculated that it might also have developed hypoxia adaptation mechanisms analogous to the genetic/epigenetic alterations acquired during tumor progression. Comparing Spalax with human and mouse p53 revealed an arginine (R) to lysine (K) substitution in Spalax (Arg-174 in human) in the DNA-binding domain, identical to known tumor associated mutations. Multiple p53 sequence alignments with 41 additional species confirmed that Arg-174 is highly conserved. Reporter assays uncovered that Spalax p53 protein is unable to induce apoptosis-regulating target genes, resulting in no expression of apaf1 and partial expression of puma, pten, and noxa. However, cell cycle arrest and p53 stabilization/homeostasis genes were overactivated by Spalax p53. Lys-174 was found critical for apaf1 expression inactivation. A DNA-free p53 structure model predicts that Arg-174 is important for dimerization, whereas Spalax Lys-174 prevents such interactions. Similar neighboring mutations found in human tumors favor growth arrest rather than apoptosis. We hypothesize that, in an analogy with human tumor progression, Spalax underwent remarkable adaptive p53 evolution during 40 million years of underground hypoxic life.

SUBMITTER: Ashur-Fabian O

PROVIDER: S-EPMC514462 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation.

Ashur-Fabian Osnat O Avivi Aaron A Trakhtenbrot Luba L Adamsky Konstantin K Cohen Meytal M Kajakaro Gadi G Joel Alma A Amariglio Ninette N Nevo Eviatar E Rechavi Gideon G

Proceedings of the National Academy of Sciences of the United States of America 20040809 33

The tumor suppressor gene p53 controls cellular response to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Inactivation of p53, found in 40-50% of human cancers, confers selective advantage under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its entire life cycle underground at decidedly lower oxygen tensions than any other mammal studied. Because a wide range of respiratory adaptations to hypoxic str ...[more]

PMID: 15302922

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Project description:Cisplatin is an important antitumor agent, but its clinical utility is often limited by multifactorial mechanism of resistance. Loss of tumor suppressor p53 function is a major mechanism that is affected by either mutation in the DNA-binding domain or dysregulation by overexpression of p53 inhibitors MDM2 and MDM4, which destabilize p53 by increasing its proteosomal degradation. In the present study, cisplatin-resistant 2780CP/Cl-16 ovarian tumor cells expressed a heterozygous, temperature-sensitive p53(V172F) mutation, which reduced p53 half-life by two- to threefold compared with homozygous wild-type (wt) p53 in parental A2780 cells. Although reduced p53 stability in 2780CP/Cl-16 cells was associated with moderate cellular overexpression of MDM2 or MDM4 (<1.5-fold), their binding to p53 was substantially enhanced (five- to eightfold). The analogous cisplatin-resistant 2780CP/Cl-24 cells, which express loss of p53 heterozygosity, retained the p53(V172F) mutation and high p53-MDM4 binding, but demonstrated lower p53-bound MDM2 that was associated with reduced p53 ubiquitination and enhanced p53 stability. The inference that p53 was unstable as a heteromeric p53(wt)/p53(V172F) complex was confirmed in 2780CP/Cl-24 cells transfected with wt p53 or multimer-inhibiting p53(L344P) mutant, and further supported by normalization of p53 stability in both resistant cell lines grown at the permissive temperature of 32.5 °C. Surprisingly, in 2780CP/Cl-16 and 2780CP/Cl-24 models, cisplatin-induced transactivity of p53 was attenuated at 37 °C, and this correlated with cisplatin resistance. However, downregulation of MDM2 or MDM4 by small interfering RNA in either resistant cell line induced p53 and restored p21 transactivation at 37 °C, as did cisplatin-induced DNA damage at 32.5 °C that coincided with reduced p53-MDM4 binding and cisplatin resistance. These results demonstrate that cisplatin-mediated p53(V172F) mutation regulates p53 stability at the normothermic temperature, but it is the increased recruitment of MDM4 by the homomeric or heteromeric mutant p53(V172F) complex that inhibits p53-dependent transactivation. This represents a novel cellular mechanism of p53 inhibition, and, thereby, induction of cisplatin resistance.

Dataset Information

Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation.

Publications

Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation.

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