Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.
Enforced expression of the antiapoptotic Bcl-2 family protein Mcl-1 promotes lymphomagenesis in the mouse; however, the functional role of Mcl-1 in human B-cell lymphoma remains unclear. We demonstrate that Mcl-1 is widely expressed in malignant B-cells, and high-level expression of Mcl-1 is required for B-lymphoma cell survival, since transfection of Mcl-1-specific antisense oligodeoxynucleotides was sufficient to promote apoptosis in Akata6 lymphoma cells. Mcl-1 was efficiently cleaved by caspases at evolutionarily conserved aspartic acid residues in vitro, and during cisplatin-induced apoptosis in B-lymphoma cell lines and spontaneous apoptosis of primary malignant B-cells. Overexpression of the Mcl-1 cleavage product that accumulated during apoptosis was sufficient to kill cells. Therefore, Mcl-1 is an essential survival molecule for B-lymphoma cells and is cleaved by caspases to a death-promoting molecule during apoptosis. In contrast to Mcl-1, Bcl-2 and Bcl-XL were relatively resistant to caspase cleavage in vitro and in intact cells. Interfering with Mcl-1 function appears to be an effective means of inducing apoptosis in Mcl-1-positive B-cell lymphoma, and the unique sensitivity of Mcl-1 to caspase-mediated cleavage suggests an attractive strategy for converting it to a proapoptotic molecule.
Michels
Jorg
J
Cancer Research UK Oncology Unit, Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK.
O'Neill
Jason W
JW
Dallman
Claire L
CL
Mouzakiti
Amalia
A
Habens
Fay
F
Brimmell
Matthew
M
Zhang
Kam Y J
KY
Craig
Ruth W
RW
Marcusson
Eric G
EG
Johnson
Peter W M
PW
Packham
Graham
G
D017209:Apoptosis / Q000502:physiology*; D001706:Biopsy; D020169:Caspases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames; D010957:Plasmids; D013873:Thionucleotides / Q000494:pharmacology
D018797:Cell Cycle Proteins; C115081:MCTS1 protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D015513:Oncogene Proteins; D013873:Thionucleotides; D020169:Caspases