Study on the relationship between rapid aging and avoidance of tumor in senescence-accelerated mouse / 中华老年医学杂志

ABSTRACT

Objective To investigate the role of p53 in the regulation of heat shock protein(Hsp)84 and 86,and the correlation of their functional imbalances with accelerated brain aging and with suppressed tumorigenesis in SAMP8 mice(senescence accelerated mouse prone 8).Methods The mRNA and protein expressions of Hsp84 and Hsp86,and protein expressions of p53 pathway-related proteins(p21 and MDM2)in hippocampus of SAMP8 mice and their control SAMR1(senescence accelerated mouse resistant 1)mice were determined.Murine Neuro-2a cells were treated with 20 μmol/L Aβ25-35,and then mRNA expressions of p53,Hsp84 and Hsp86 in these cells were detected.Neuro-2a cells were co-transfected with p53 siRNA and pHsp84-Luc or pHsp86-Luc plasmid and treated with 20 μmol/L Aβ25-35,then promoter activity of Hsp84 and Hsp86 were detected in these cells.After co-transfection with pcDNA3.1-p53 or pcDNA3.1-p53DD and pHsp84-Luc or pHsp86-Luc plasmids,the neuro-2a cells were treated with 20 μmol/L Aβ25-35.Then promoter activity of Hsp84 and Hsp86 were detected in these cells at different concentrations of p53.Results The mRNA levels of Hsp84 and Hsp86 in the hippocampus of SAMP8 mice were significantly declined,which were 13.51% and 16.13% of SAMR1 mice,respectively(all P<0.01).Compared with the SAMR1 mice,the protein expressions of Hsp84 and Hsp86 in the hippocampus of SAMP8 mice were obviously declined(all P<0.01).Whereas,p53 pathway-related protein p21 expression was increased and MDM2 expression was decreased(all P<0.01).The mRNA expression of p53 in AD cells was significantly increased by 58%(P<0.01),whereas Hsp84 and Hsp86 mRNA levels were significantly decreased by 32% and 41%,respectively as compared with the normal cells(all P<0.05).Inhibition of p53 in AD cells could increase promoter activity of Hsp84 and Hsp86 significantly in a concentration-dependent manner(both P<0.05),whereas overexpression of p53 in the cells could lead to decreased promoter activity of them in a concentration-dependent manner(both P<0.05).Conclusions The p53 can negatively regulate the expressions of Hsp84 and Hsp86.The activity of p53/p21 pathway is increased,while Hsp84 and Hsp86 are inhibited in the brain of SAMP8 mice.Functional imbalance between p53 and Hsp84/86 might be the part of reasons causing accelerated aging and suppressed tumorigenesis in SAMP8 mice.