Stability of the nuclear protein turnover during cellular senescence of human fibroblasts.

The accumulation of oxidized proteins is one of the highlights of age-related changes of cellular metabolism and happens at least partially as a result of a decline in the activity of intracellular proteases (e.g., the proteasome). Because the proteasome is located in numerous cellular compartments, we tested whether and to which extent the proteasome and the protein turnover changes in the cytosolic compartment and in the nucleus of proliferating fibroblasts. We demonstrated that the activity of the proteasomal system declines during proliferative senescence of human fibroblasts in the cytosol dramatically, whereas it is stable within the nucleus. It could be demonstrated in both compartments that an accumulation of oxidized proteins occurs. After oxidative stress, a short timed activation of the proteasomal system in the nucleus occurs. This activation was accompanied by an increase in the protein turnover in response to oxidative stress, which was also present in the nucleus of senescent cells. Taking into account that the nuclear/cytosol ratio of the proteasome content declines during proliferative senescence, we postulated that the senescence-related changes in the cytosolic proteasomal system are more pronounced and that the nuclear proteasomal system is only marginally affected by the senescence process.