Characterisation of Mcl-1 cleavage during apoptosis of haematopoietic cells.
Mcl-1 is essential for normal haematopoiesis, being required for lymphocyte development and maintenance. Its role in haematopoietic differentiation and development is associated with its function as an anti-apoptotic member of the Bcl-2 family of proteins although the underlining mechanism is poorly understood. We have characterized caspase cleavage of the Mcl-1 protein during apoptosis. Caspase cleavage resulted in the removal of the PEST regions from the protein and generation of a fragment containing the BH-1, -2 and -3 homology domains. Removal of the PEST regions did not appear to alter Mcl-1 stability, suggesting that these regions are not responsible for Mcl-1's short half-life. In addition, unlike cleavage of Bcl-2 and Bcl-X(L), which resulted in pro-apoptotic fragments, cleaved forms of Mcl-1 were unable to induce apoptosis. This novel regulation of Mcl-1 may have important implications not only for its role in apoptosis but also for the essential role it plays in the differentiation and development of haematopoietic cells.
Clohessy
John G
JG
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, UK.
Zhuang
Jianguo
J
Brady
Hugh J M
HJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases