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...

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