Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes.

摘要: We recently reported increased sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Here, we show that only specific—not nonspecific—proteasomal inhibitors can discriminate between malignant and normal in inducing response. Indeed, lactacystin its active metabolite clasto -lactacystin β-lactone induced CLL but not lymphocytes. This difference was completely abolished when tripeptide aldehydes such as MG132 or LLnL (which also inhibit calpains) were used less specific proteasomal inhibitors. Moreover, B-CLL cells exhibited a constitutive altered ubiquitin-proteasome system, including threefold higher chymotrypsin-like activity high levels nuclear ubiquitin-conjugated proteins compared with Interestingly, displayed proteolytic regulation wild-type p53, an factor be substrate for system. Nuclear p53 accumulated after treatment at discriminating concentration malignant, normal, In contrast, stabilized undergoing apoptosis, indicating is regulated mainly calpains work raises possibility two different pathways controlling stability may pathologically imbalanced. could result modification apoptosis control, since CLL-lymphocytes highly upregulated which controls among other factors, correlated propensity these triggered