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p53 gene cloning and response to hypoxia in the plateau zokor, Myospalax baileyi

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The plateau zokor (Myospalax baileyi) is a specialized subterranean rodent that lives on the Qinghai-Tibet Plateau. The species has evolved a series of strategies to adapt to its hypoxic environment and hypercapnia. p53 is a tumour suppressor gene that plays a crucial role in the cellular response to hypoxia by inducing cell cycle arrest, cell apoptosis, DNA damage repair and angiogenesis. To investigate the sequence characteristics of p53 and the response to hypoxia in plateau zokor, we cloned the p53 coding DNA sequence, analysed it, and measured the expression level of p53 at different altitudes in plateau zokor and rats. Our results show that the coding DNA sequence is 1179 bp, consisting of 392 amino acid residues. Compared to human p53, the subterranean rodents have two mutation sites in common with the human hotspots in the DNA-binding domain. Compared to subterranean rodents, plateau zokor have a mutation at residue 309. In addition, subterranean rodents have two convergent sites at residues 78 and 84. The expression levels of p53 in plateau zokor tissues increase significantly from 2260 m to 3300 m, but there was no significant difference in rats at those altitudes. Our results suggest that subterranean rodents have two mutation sites in common with the human hotspots in the DNA-binding domain, the mutation of Gly309Asp is a unique mutation site of plateau zokor p53, and there are two convergent sites enhancing subterranean rodent adaptation to hypoxic conditions. In addition, p53 is sensitive to the oxygen concentration in plateau zokor, and hypoxia upregulates the levels of p53. Generally, plateau zokor use this strategy to adapt to a hypoxic environment.

Affiliations: 1: 1State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, 251 Ningda Road, Xining, Qinghai 810016, China ; 2: 2Research Center for High Altitude Medicine, Qinghai University, 251 Ningda Road, Xining, Qinghai 810016, China ; 3: 3College of Medical, Qinghai University, 251 Ningda Road, Xining, Qinghai 810016, China ; 4: 4College of Eco-Environmental Engineering, Qinghai University, 251 Ningda Road, Xining, Qinghai 810016, China

+These authors contributed equally to this work.
*Corresponding author; e-mail:

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1. Arieli R., Ar A. (1981) "Heart rate responses of the mole rat (Spalax ehrenbergi) in hypercapnic, hypoxic, and cold conditions". Physiol. Zool., Vol 54, 14-21. [Crossref]
2. Arieli R., Heth G., Nevo E., Hoch D. (1986) "Hematocrit and hemoglobin concentration in four chromosomal species and some isolated populations of actively speciating subterranean mole rats in Israel". Experientia, Vol 42, 441-443. [Crossref]
3. Ashur-Fabian O., Avivi A., Trakhtenbrot L., Adamsky K., Cohen M., Kajakaro G., Joel A., Amariglio N., Nevo E., Rechavi G. (2004) "Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation". Proc. Natl Acad. Sci. USA, Vol 101, 12236-12241. [Crossref]
4. Avivi A., Ashur-Fabian O., Joel A., Trakhtenbrot L., Adamsky K., Goldstein I., Amariglio N., Rechavi G., Nevo E. (2007) "p53 in blind subterranean mole rats – loss-of-function versus gain-of-function activities on newly cloned Spalax target genes". Oncogene, Vol 26, 2507-2512. [Crossref]
5. Bargonetti J., Manfredi J.J., Chen X., Marshak D.R., Prives C. (1993) "A proteolytic fragment from the central region of p53 has marked sequence-specific DNA-binding activity when generated from wild-type but not from oncogenic mutant p53 protein". Gene Dev., Vol 7, 2565-2574. [Crossref]
6. Ben-Shlomo R., Maeda N. (1989) "Haptoglobin DNA polymorphism in subterranean mole rats of the Spalax ehrenbergi superspecies in Israel". Heredity, Vol 62, 85-90. [Crossref]
7. Buffenstein R. (2008) "Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species". J. Comp. Physiol. B, Vol 178, 439-445. [Crossref]
8. Buffenstein R., Jarvis J.U.M. (2002) "The naked mole rat – a new record for the oldest living rodent". Sci. Aging Knowl. Environ., Vol 2002, pe7. DOI:10.1126/sageke.2002.21.pe7. [Crossref]
9. Bullock A.N., Fersht A.R. (2001) "Rescuing the function of mutant p53". Nat. Rev. Cancer, Vol 1, 68-76. [Crossref]
10. Cho Y., Gorina S., Jeffrey P.D., Pavletich N.P. (1994) "Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations". Science, Vol 265, 346-355. [Crossref]
11. Corpet F. (1988) "Multiple sequence alignment with hierarchical clustering". Nucleic Acids Res., Vol 16, 10881-10890. [Crossref]
12. Delaney M.A., Nagy L., Kinsel M.J., Treuting P.M. (2013) "Spontaneous histologic lesions of the adult naked mole rat (Heterocephalus glaber): a retrospective survey of lesions in a zoo population". Vet. Pathol., Vol 50, 607-621. [Crossref]
13. Edoute Y., Arieli R., Nevo E. (1988) "Evidence for improved myocardial oxygen delivery and function during hypoxia in the mole rat". J. Comp. Physiol. B, Vol 158, 575-582. [Crossref]
14. Edrey Y.H., Casper D., Huchon D., Mele J., Gelfond J.A., Kristan D.M., Nevo E., Buffenstein R. (2012) "Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity". Aging Cell, Vol 11, 213-222. [Crossref]
15. El-Deiry W.S. (1998) "Regulation of p53 downstream genes". Semin. Cancer Biol., Vol 8, 345-357. [Crossref]
16. Fan N.C., Shi Y.Z. (1982) "A revision of the zokors of subgenus Eospalax". Acta Theriol. Sin., Vol 2, 183-199.
17. Fang X., Nevo E., Han L., Levanon E.Y., Zhao J., Avivi A., Larkin D., Jiang X., Feranchuk S., Zhu Y., Fishman A., Feng Y., Sher N., Xiong Z., Hankeln T., Huang Z., Gorbunova V., Zhang L., Zhao W., Wildman D.E., Xiong Y., Gudkov A., Zheng Q., Rechavi G., Liu S., Bazak L., Chen J., Knisbacher B.A., Lu Y., Shams I., Gajda K., Farre M., Kim J., Lewin H.A., Ma J., Band M., Bicker A., Kranz A., Mattheus T., Schmidt H., Seluanov A., Azpurua J., McGowen M.R., Jacob E.B., Li K., Peng S., Zhu X., Liao X., Li S., Krogh A., Zhou X., Brodsky L., Wang J. (2014) "Genome-wide adaptive complexes to underground stresses in blind mole rats Spalax". Nat. Commun., Vol 5, 3966. DOI:10.1038/ncomms4966.
18. Fels D.R., Koumenis C. (2005) "HIF-1α and i: the ODD couple?" Trends Biochem. Sci., Vol 30, 426-429. [Crossref]
19. Freed-Pastor W.A., Prives C. (2012) "Mutant p53: one name, many proteins". Gene Dev., Vol 26, 1268-1286. [Crossref]
20. Giaccia A.J., Kastan M.B. (1998) "The complexity of p53 modulation: emerging patterns from divergent signals". Gene Dev., Vol 12, 2973-2983. [Crossref]
21. Graeber T.G., Osmanian C., Jacks T., Housman D.E. (1996) "Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours". Nature, Vol 379, 88-91. [Crossref]
22. Gurnett A.M., O’Connell J.P., Harris D.E., Lehmann H., Joysey K.A., Nevo E. (1984) "The myoglobin of rodents: Lagostomus maximus (viscacha) and Spalax ehrenbergi (mole rat)". J. Protein Chem., Vol 3, 445-454. [Crossref]
23. Hansson L.O., Friedler A., Freund S., Rüdiger S., Fersht A.R. (2002) "Two sequence motifs from HIF-1α bind to the DNA-binding site of p53". Proc. Natl Acad. Sci. USA, Vol 99, 10305-10309. [Crossref]
24. Hernandez I., Maddison L.A., Wei Y., DeMayo F., Petras T., Li B., Gingrich J.R., Rosen J.M., Greenberg N.M. (2003) "Prostate-specific expression of p53 R172L differentially regulates p21, Bax, and mdm2 to inhibit prostate cancer progression and prolong survival". Mol. Cancer Res., Vol 1, 1036-1047.
25. Hollstein M., Rice K., Greenblatt M.S., Soussi T., Fuchs R., Sørlie T., Hovig T., Smith-Sorensen B., Montesano R., Harris C.C. (1994) "Database of p53 gene somatic mutations in human tumors and cell lines". Nucleic Acids Res., Vol 22, 3551-3555.
26. Huang L.E., Gu J., Schau M., Bunn H.F. (1998) "Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway". Proc. Natl Acad. Sci. USA, Vol 95, 7987-7992. [Crossref]
27. Jeanmougin F., Thompson J.D., Gouy M., Higgins D.G., Gibson T.J. (1998) "Multiple sequence alignment with Clustal X". Trends Biochem. Sci., Vol 23, 403-405. [Crossref]
28. Ke Q., Costa M. (2006) "Hypoxia-inducible factor-1 (HIF-1)". Mol. Pharmacol., Vol 70, 1469-1480. [Crossref]
29. Kim E.B., Fang X., Fushan A.A., Huang Z., Lobanov A.V., Han L., Marino S.M., Sun X., Turanov A.A., Yang P., Yim S.H., Zhao X., Kasaikina M.V., Stoletzki N., Peng C., Polak P., Xiong Z., Kiezun A., Zhu Y., Chen Y., Kryukov G.V., Zhang Q., Peshkin L., Yang L., Bronson R.T., Buffenstein R., Wang B., Han C., Li Q., Chen L., Zhao W., Sunyaev S.R., Park T.J., Zhang G., Wang J., Gladyshev V.N. (2011) "Genome sequencing reveals insights into physiology and longevity of the naked mole rat". Nature, Vol 479, 223-227. [Crossref]
30. Kinzler K.W., Vogelstein B. (1996) "Lessons from hereditary colorectal cancer". Cell, Vol 87, 159-170. [Crossref]
31. Klein G. (2004) "Cancer, apoptosis, and nonimmune surveillance". Cell Death Differ., Vol 11, 13-17. [Crossref]
32. Kleinschmidt T., Nevo E., Braunitzer G. (1984) "The primary structure of the hemoglobin of the mole rat (Spalax ehrenbergi, Rodentia, chromosome species 60)". Hoppe Seyler Z. Physiol. Chem., Vol 365, 531-538. [Crossref]
33. Kleinschmidt T., Nevo E., Goodman M., Braunitzer G. (1985) "Mole rat hemoglobin: primary structure and evolutionary aspects in a second karyotype of Spalax ehrenbergi, Rodentia, (2n=52)". Biol. Chem. Hoppe Seyler, Vol 366, 679-686. [Crossref]
34. Koumenis C., Alarcon R., Hammond E., Sutphin P., Hoffman W., Murphy M., Derr J., Taya Y., Lowe S.W., Kastan M., Giaccia A. (2001) "Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation". Mol. Cell. Biol., Vol 21, 1297-1310. [Crossref]
35. Kumar S., Stecher G., Tamura K. (2016) "MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets". Mol. Biol. Evol., Vol 33, 1870-1874. [Crossref]
36. Li D.H. (1989) Economic Animal Fauna of Qinghai. Qinghai People’s Publishing House, Xining, China.
37. Livak K.J., Schmittgen T.D. (2001) "Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method". Methods, Vol 25, 402-408. [Crossref]
38. Masson N., Willam C., Maxwell P.H., Pugh C.W., Ratcliffe P.J. (2001) "Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation". EMBO J., Vol 20, 5197-5206. [Crossref]
39. Menendez D., Inga A., Resnick M.A. (2006) "The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes". Mol. Cell. Biol., Vol 26, 2297-2308. [Crossref]
40. Nevo E. (1999) Mosaic Evolution of Subterranean Mammals: Regression, Progression, and Global Convergence. Oxford University Press, Oxford, UK.
41. Nevo E. (2011) "Evolution under environmental stress at macro- and microscales". Genome Biol. Evol., Vol 3, 1039-1052. [Crossref]
42. Nevo E., Ivanitskaia E., Beiles A. (2001) Adaptive Radiation of Blind Subterranean Mole Rats: Naming and Revisiting the Four Sibling Species of the Spalax ehrenbergi Superspecies in Israel: Spalax galili (2n = 52), S. golani (2n = 5), S. carmeli (2n = 58) and S. judaei (2n = 60). Backhuys Publishers, Leiden, Netherlands.
43. Pavletich N.P., Chambers K.A., Pabo C.O. (1993) "The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots". Gene Dev., Vol 7, 2556-2564. [Crossref]
44. Pevet P., Heth G., Hiam A., Nevo E. (1984) "Photoperiod perception in the blind mole rat (Spalax ehrenbergi, Nehring): involvement of the Harderian gland, atrophied eyes, and melatonin". J. Exp. Zool., Vol 232, 41-50. [Crossref]
45. Resnick M.A., Inga A. (2003) "Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity". Proc. Natl Acad. Sci. USA, Vol 100, 9934-9939. [Crossref]
46. Resnick M.A., Tomso D., Inga A., Menendez D., Bell D. (2005) "Functional diversity in the gene network controlled by the master regulator p53 in humans". Cell Cycle, Vol 4, 1026-1029. [Crossref]
47. Saitou N., Nei M. (1987) "The neighbor-joining method: a new method for reconstructing phylogenetic trees". Mol. Biol. Evol., Vol 4, 406-425.
48. Sánchez-Puig N., Veprintsev D.B., Fersht A.R. (2005) "Binding of natively unfolded HIF-1α ODD domain to p53". Mol. Cell., Vol 17, 11-21. [Crossref]
49. Shams I., Avivi A., Nevo E. (2004) "Hypoxic stress tolerance of the blind subterranean mole rat: expression of erythropoietin and hypoxia-inducible factor 1α". Proc. Natl Acad. Sci. USA, Vol 101, 9698-9703. [Crossref]
50. Shams I., Nevo E., Avivi A. (2005) "Erythropoietin receptor spliced forms differentially expressed in blind subterranean mole rats". FASEB J., Vol 19, 1749-1751. [Crossref]
51. Shao Y., Li J.X., Ge R.L., Zhong L., Irwin D.M., Murphy R.W., Zhang Y.P. (2015) "Genetic adaptations of the plateau zokor in high-elevation burrows". Sci. Rep., Vol 5, 17262. DOI:10.1038/srep17262.
52. Tamura K., Peterson D., Peterson N., Stecher G., Nei M., Kumar S. (2011) "MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods". Mol. Biol. Evol., Vol 28, 2731-2739. [Crossref]
53. Thut C.J., Chen J.L., Klemm R., Tijan R. (1995) "p53 transcriptional activation mediated by coactivators TAF (II) 40 and TAF (II) 60". Science, Vol 267, 100-104. [Crossref]
54. Tian X., Azpurua J., Hine C., Vaidya A., Myakishev-Rempel M., Ablaeva J., Mao Z.Y., Nevo E., Gorbunova V., Seluanov A. (2013) "High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat". Nature, Vol 499, 346-349. [Crossref]
55. Vousden K.H., Lu X. (2002) "Live or let die: the cell’s response to p53". Nat. Rev. Cancer, Vol 2, 594-604. [Crossref]
56. Walker K.K., Levine A.J. (1996) "Identification of a novel p53 functional domain that is necessary for efficient growth suppression". Proc. Natl Acad. Sci. USA, Vol 93, 15335-15340. [Crossref]
57. Wang M.Y., Zhao Y., Zhang S.T., Chen X.Q., Du J.Z. (2013) "The regulation of expression for p53 and its target genes in simulate hypoxia". China J. Appl. Physiol., Vol 29, 136-138.
58. Wang X.J., Wei D.B., Wei L., Qi X.Z., Zhu S.H., Rao X.F. (2008a) "Characteristics of pulmonary acinus structure in the plateau zokor (Myospalax baileyi) and plateau pika (Ochotona curzniae)". Acta Zool. Sin., Vol 54, 531-539.
59. Wang X.J., Wei D.B., Wei L., Zhang J.M., Yu H.Y. (2008b) "Physiological character of erythrocyte adapting to hypoxia in plateau zokor and plateau pika". Sichuan J. Zool., Vol 27, 1100-1103.
60. Wang Z.L., Chen Y., Yang J., Chen W.J., Zhang Y.M., Zhao X.Q. (2012) "cDNA cloning and expression of erythropoietin in the plateau zokor (Myospalax baileyi) from the Qinghai-Tibet Plateau". Chin. Sci. Bull., Vol 57, 997-1006. [Crossref]
61. Wang Z.W., Zeng J.X., Han Y.C. (1979) "Studies on gas metabolism of pika (Ochotona) and plateau zokor (Myospalax baileyi)". Acta Zool. Sin., Vol 25, 75-84.
62. Wei D.B., Ma J.B. (2001a) "Comparison of the content of myoglobin and lactate dehydrogenase in cardiac and skeleton muscle of plateau zorkor and mouse". J. Qinghai Univ., Vol 19, 20-21.
63. Wei D.B., Wei L. (2001b) "The mensuration results of the number of red cell and the content of hemoglobin and myoglobin in plateau zokor". J. Qinghai Univ., Vol 19, 1-2.
64. Wei D.B., Wei L., Zhang J.M., Yu H.Y. (2006a) "Blood-gas properties of plateau zokor (Myospalax baileyi)". Comp. Biochem. Phys. A, Vol 145, 372-375. [Crossref]
65. Wei L., Yu H.Y., Zhang J.M., Mu J.Y., Wei D.B. (2006b) "Seasonal changes of myoglobin in cardiac and skeleton muscle of Plateau Zokor (Myospalax baileyi)". J. Qinghai Univ., Vol 24, 34-36.
66. Widmer H.R., Hoppeler H., Nevo E., Taylor C.R., Weibel E.R. (1997) "Working underground: respiratory adaptations in the blind mole rat". Proc. Nat. Acad. Sci. USA, Vol 94, 2062-2067. [Crossref]
67. Yang J., Li J.G., He J.P., Zhang Y.L. (2006) "Blood composition and its relationship with hypoxia adaptation in Gansu Zokor". Chin. J. Zool., Vol 41, 112-115.
68. Yang Z.H. (2007) "PAML 4: phylogenetic analysis by maximum likelihood". Mol. Biol. Evol., Vol 24, 1586-1591. [Crossref]
69. Zhang J., Kumar S. (1997) "Detection of convergent and parallel evolution at the amino acid sequence level". Mol. Biol. Evol., Vol 14, 527-536. [Crossref]
70. Zhang J.Z., Nielsen R., Yang Z.H. (2005) "Evaluation of an improved branch-site likelihood method for detecting positive selection at the molecular level". Mol. Biol. Evol., Vol 22, 2472-2479. [Crossref]
71. Zhao K., Chai X., Johnston K., Clements A., Marmorstein R. (2001) "Crystal structure of the mouse p53 core DNA-binding domain at 2.7 Å resolution". J. Biol. Chem., Vol 276, 12120-12127. [Crossref]
72. Zhao Y., Ren J.L., Wang M.Y., Zhang S.T., Liu Y., Li M., Cao Y.B., Zu H.Y., Chen X.Q., Wu C.I., Nevo E., Chen X.Q., Du J.Z. (2013) "Codon 104 variation of p53 gene provides adaptive apoptotic responses to extreme environments in mammals of the Tibet plateau". Proc. Natl Acad. Sci. USA, Vol 110, 20639-20644. [Crossref]
73. Zheng Y.N., Zhu R.J., Wang D.W., Wei L., Wei D.B. (2011) "Gene coding and mRNA expression of vascular endothelial growth factor as well as microvessel density in brain of plateau zokor: comparison with other rodents". Acta Physiol. Sin., Vol 63, 155-163.

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