Reciprocal protection of Mcl-1 and Bim from ubiquitin-proteasome degradation.
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 shMcl-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 Mcl-1 and Bim confers to themselves mutual protection.
INSERM, UMR601, Département de recherche en Cancérologie, 9, quai Moncousu, Nantes F-44000, France.
Soraya
S
Wuillème-Toumi
Valérie
V
Trichet
Patricia
P
Gomez-Bougie
Catherine
C
Gratas
Régis
R
Bataille
Martine
M
Amiot
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000201:enzymology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D025801:Ubiquitin / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex