Survival of multiple myeloma cells is essentially dependent on Mcl-1 protein that neutralizes the pro-apoptotic function of Bim and prevents activation of death effectors. To clarify the relationship between Mcl-1 and Bim, we generated cell lines silenced for Mcl-1 (shMcl-1) or Bim (shBim). We demonstrate that Mcl-1 and Bim proteins are concomitantly down-regulated in either shBim or shMcl-1 cells. We show that the down-regulation of either Mcl-1 in shBim or Bim in hMcl-1 cells is not due to a transcriptional event, but results from post-translational regulation. Indeed, the multi-ubiquitinated forms of Mcl-1 or Bim are increased in shBim and shMcl-1 cells, respectively, indicating proteasome degradation. Since Mcl-1/Bim complexes are predominant in myeloma cells the down-regulation of Mcl-1 by shRNA leads to unliganded Bim sensitive to degradation and reciprocally for unliganded Mcl-1 in shBim cells. Finally, our results support that the interaction between McI-1 and Bim confers to themselves mutual protection. (C) 2007 Elsevier Inc. All rights reserved.