Codon 104 variation of p53 gene provides adaptive apoptotic responses to extreme environments in mammals of the Tibet plateau

Abstract

Mutational changes in p53 correlate well with tumorigenesis. Remarkably, however, relatively little is known about the role that p53 variations may play in environmental adaptation. Here we report that codon asparagine-104 (104N) and glutamic acid-104 (104E), respectively, of the p53 gene in the wild zokor (Myospalax baileyi) and root vole (Microtus oeconomus) are adaptively variable, meeting the environmental stresses of the Tibetan plateau. They differ from serine-104 (104S) seen in other rodents, including the lowland subterranean zokor Myospalax cansus, and from serine 106 (106S) in humans. Based on site-directed mutational analysis in human cell lines, the codon 104N variation in M. baileyi is responsible for the adaptive balance of the transactivation of apoptotic genes under hypoxia, cold, and acidic stresses. The 104E p53 variant in Microtus oeconomus suppresses apoptotic gene transactivation and cell apoptosis. Neither 104N nor 104E affects the cell-cycle genes. We propose that these variations in p53 codon 104 are an outcome of environmental adaptation and evolutionary selection that enhance cellular strategies for surviving the environmental stresses of hypoxia and cold (in M. baileyi and M. oeconomus) and hypercapnia (in M. baileyi) in the stressful environments of the Qinghai-Tibet plateau.T he regulatory mechanisms of p53 mutation related to tumorigenesis have been widely studied and elucidated (1, 2). Notably, however, p53 evolution and adaptation to environmental stresses have not attracted as much attention. Current studies show that p53 is a master sensor and regulator in response to various stressors, such as DNA damage and hypoxia (3-6). Activation of p53 by stresses results in cell-cycle arrest, DNA repair, senescence, or apoptosis in which a series of p53 target genes are involved to maintain genomic integrity (2). The p53 variations associated with environmental stresses have been described in the Mexican salamander axolotl Ambystoma mexicanum and the Israeli blind subterranean mole rat (Spalax judaei; hereafter, S.j.) (7-9).For animals existing on high plateaus, hypoxia and cold serve as strong environmental selective pressures generating adaptive complexes to cope with these stresses. Animals that have evolved on plateaus adopt various strategies involving multiple variations to regulate a series of genes (3, 7). The zokor (Myospalax baileyi, Thomas, 1911; hereafter M.b.) and root vole (Microtus oeconomus, Pallas, 1776; hereafter M.o.) are the dominant native mammals living on the alpine meadow of the Qinghai-Tibet Plateau of China at altitudes of 3,000-4,500 m (equivalent to 11.0-13.0% O 2 at sea level). M.b. is genetically close to Myospalax cansus (Lyon, 1907; hereafter, M.c.), which lives in subterranean burrows at a lower altitude of about 800 m in the lowland of western China. M.b. and M.c. spend their entire life cycle at 70-250 cm underground with significantly low O 2 and high CO 2 levels in their burrows (10). Since the collision of the Indian and the Eurasian plates during the...

Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

“…The liver and pancreas were immediately removed, frozen in liquid nitrogen, and stored at 280°C until use. Isolated islets in the hypoxia group were incubated in 5% CO 2 and various O 2 conditions delivered by the hypoxia chamber (ProOx model P110 and ProCO 2 model P120 systems; BioSpherix, Lacona, NY) (24).…”

Adaptive methylation regulation of p53 pathway in sympatric speciation of blind mole rats, Spalax

“…Modifications of p53 in different levels during adaptive evolution confer the animal's selective advantage by regulating adaptive cell fates. Our recent study demonstrated that variation of p53 is important for adapting to a variety of environmental stresses, including hypoxia, temperature, and pH changes (12).…”

p53 gene discriminates two ecologically divergent sister species of pine voles

“…The p53 mutation found in Spalax-R174K in the human protein-was shown to be sufficient to affect the transcriptional activity of both Spalax and human P53 protein (Ashur-Fabian et al, 2004;Avivi et al, 2007). Other codon variations in P53 were shown to provide adaptive responses to a wide range of environmental cues in other species (Villiard et al, 2007;Zhao et al, 2013), strengthening the hypothesis that P53 protein may adapt in structure and function in accordance with ecological stress (Zhao et al, 2013).…”

“…In sympatry, both the voles occupy a specialized ecological niche, in which soil characteristics seem to be particularly relevant (Borghi et al, 1994;Santos et al, 2009a, b;Santos et al, 2010;Santos et al, 2011). Niche specialization may involve distinctive physiological and genetic adaptations (Singh et al, 2009;Hadid et al, 2013), probably species and stress environmental specific, as suggested with the S104E variation observed within the P53 protein of high-altitude M. oeconomus or the R174K mutation in P53 of the subterranean Spalax (Ashur-Fabian et al, 2004;Zhao et al, 2013). The D228E mutation could similarly have favoured M. duodecimcostatus as this species expanded its territory in the Iberian Peninsula and evolved a more pronounced fossorial behaviour than M. lusitanicus.…”