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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Amariglio, Ninette Adamsky, Konstantin Cohen, Meytal Nevo, Eviatar Ashur-fabian, Osnat Trakhtenbrot, Luba Kajakaro, Gadi Joel, Alma Avivi, Aaron Rechavi, Gideon |
| Description | Author Affiliation: Ashur-Fabian O ( Pediatric Hematology-Oncology, Safra Children's Hospital, The Chaim Sheba Medical Center, Tel-Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 33 |
| Volume Number | 101 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2004-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Evolution, Molecular Genes, P53 Mole Rats Genetics Mutation Neoplasms Adaptation, Physiological Amino Acid Sequence Amino Acid Substitution Animals Apoptosis DNA Anoxia Mice Models, Genetic Models, Molecular Physiology Molecular Sequence Data Mutagenesis, Site-Directed Protein Conformation Sequence Homology, Amino Acid Species Specificity Tumor Suppressor Protein P53 Chemistry Comparative Study Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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