ABSTRACT
To provide an improved understanding of the molecular basis of the aging process, it is necessary to measure biological age on a tissue-specific basis. The role of DNA damage has emerged as a significant mechanism for determination of life span, and DNA repair genes and stress-response genes are also implicated in the aging process. In the present study, we investigated the changes of DNA-PK activity, especially Ku activity, in the various tissues including kidney, lung, testis and liver during aging and its correlation with mtHSP70 expression. We showed that the modulation of Ku activity during the aging process was highly tissue-specific as shown with highly impaired Ku activity in testis and unaffected Ku activity in liver with age, and the level of Ku70 or Ku80 was differentially expressed in each aging tissue. We found also that age-associated alteration of Ku70/80 was prevented or not prevented by caloric restriction (CR) in a tissue-specific manner. Age-related decline in Ku70 during the aging process was associated with the increase of mtHSP70, which could play a role as a predictive marker for aging related to Ku regulation, and CR retarded aging-induced mtHSP70.
Subject(s)
Aging/metabolism , Antigens, Nuclear/metabolism , Caloric Restriction , DNA-Binding Proteins/metabolism , HSP70 Heat-Shock Proteins/metabolism , Animals , Antigens, Nuclear/physiology , Cells, Cultured , DNA-Binding Proteins/physiology , Ku Autoantigen , Male , Mice , Rats , Rats, Inbred F344 , Tissue DistributionABSTRACT
Since DNA-dependent protein kinase (DNA-PK) has been known to play a protective role against drug-induced apoptosis, the role of DNA-PK in the regulation of mitochondrial heat shock proteins by anticancer drugs was examined. The levels of basal and drug-induced mitochondrial heat shock proteins of drug-sensitive parental cells were higher than those of multidrug-resistant (MDR) cells. We also demonstrated that the development of MDR might be correlated with the increased expression of Ku-subunit of DNA-PK and concurrent down-regulation of mitochondrial heat shock proteins. The basal mtHsp70 and Hsp60 levels of Ku70(-/-) cells, which were known to be sensitive to anticancer drugs, were higher than those of parental MEF cells, but conversely these mitochondrial heat shock proteins of R7080-6 cells over-expressing both Ku70 and Ku80 were lower than those of parental Rat-1 cells. Also, the mtHsp70 and Hsp60 levels of DNA-PKcs-deficient SCID cells were higher than those of parental CB-17 cells. Our results suggest the possibility that mitochondrial heat shock protein may be one of determinants of drug sensitivity and could be regulated by DNA-PK activity.
