The Analysis Of Varivation And Anontosis In MDM2/MDMX From Mvosnalax Baileyi And Myospalax Cansus

Myospalax baileyi(M.b),a subterranean zokor lived at Tibet plateau,faces extremely environmental stresses(hypoxia,hypercapnia and cold temperature).Myospalax cansus(M.c)is also a subterranean zokor and faces same environmental stresses,but lived at plain.Previous studies of our lab have demonstrated p53 variation of M.b and Spalax(Israel blind mole)contribute to environmental adaptation.MDM2 and MDMX are the crucially negative regulators,which can mediate the ubiquitination degradation of p53.Furthermore,there is an auto negative regulation loop between MDM2/X and p53.In DNA damage stress,MDM2/X will mediate the ubiquitination degradation of themselves,and promote p53 expression.In tumor microenvironment,HIF-2alpha inhibits p53 phosphorylation and stabilization,promotes MDM2 phosphorylation and nuclear localization to degrade p53.This research has cloned MDMX-CDS sequence of M.b,M.c,Microtus oeconomus and Microtus ochrogaster;HIF-2alpha-CDS sequence of M.c;MDM2 promoter sequence of M.b and M.c.The sequence comparison of MDMX and HIF-2alpha has found the homology of M.b and M.c is extremely high,and the same variation exist in M.b and M.c.What’s more,the methylation levels of MDM2 promoter are different in M.b and M.c,which impact the mRNA expression levels.The mRNA level in lung,speleen and liver of M.b and M.c are significant increased than SD rat,but without distinct negative regulation loop between MDM2/X and p53.And,co-transfection of M.b MDM2/X and p53 in H1299 cell induce a significant reduced apoptosis than control group(only M.b p53)under hypoxia,and M.c p53 can decrease cell apoptosis under normoxia.Moreover,the T480S variation of M.b HIF-2alpha increases HIF-2alpha transcription activity,but non effect on reducing cell apoptosis.In summary,M.b and M.c gene variations is one of the outcome in environmentally positive selection.There is a special mechanism in MDM2/X-p53 loop of M.b,which can promote the anti-apoptosis function of p53 under hypoxia,and the HIF-2alpha variation associated with its transcription activity.These results have suggested MDM2,MDMX,p53 and HIF-2alpha play important roles in environmental adaptation.