E.S. Gonos

We have developed conditionally immortalized cell lines and we have cloned several senescence associated genes. Analysis of the function of one of the isolated genes (ApoJ), suggests that it is a novel survival factor. ApoJ is found over-expressed in vitro under a variety of stress conditions and in vivo in patients suffering from various age-related diseases. Stable over-expression of ApoJ inhibits apoptosis and its inhibition by RNA interference sensitizes cells to cytotoxicity. Moreover, we have shown that ApoJ is implicated to DNA repair processes as it interacts with the DNA helicases Ku70/80. We have also studied proteasome function in replicative senescence and cell survival. We have observed reduced levels of proteasomal peptidase activities in senescent cells that is accompanied by a decrease in the level of both 20S and 26S complexes. Partial inhibition of proteasomes in young cells caused by treatment with specific inhibitors induced a senescence-like phenotype and stable over-expression of beta-1 and beta-5 subunits in established cell lines was shown to induce elevated expression levels of beta-1 subunit in beta-5 transfectants and vice-versa. Transfectants possess increased proteasome activities and most importantly, increased capacity to cope better with various stresses.

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