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Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage

Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage
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.
apoptosis, Mcl-1, antisense, non-hodgkin's lymphoma, Bcl-2, caspase
0950-9232
4818-4827
Michels, J.
01124646-b096-4cec-86c9-2cbddaad8e74
O'Neill, Jason W.
1abf1e09-b5d7-499f-9d2f-1d20d1007142
Dallman, Claire L.
d0b9f211-1d21-4b5e-bd25-ec9dd56492fe
Mouzakiti, Amalia
b90571cd-47a7-4156-b69b-ec0bf0e17106
Habens, Fay
3e4cce4b-4521-4702-9582-f817d25aad37
Brimmell, Matthew
4bb675a5-c3f0-4ddb-ae49-d39257ba79e1
Zhang, Kam Y.G.
d4816828-fe84-462a-bf8a-c1f0df2c4158
Craig, Ruth W.
3449fcc5-3f49-406d-8b65-650b53b11784
Marcusson, Eric G.
905194c7-075f-4089-aedf-ccd4e5f8e0e2
Johnson, Peter W.M.
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Michels, J.
01124646-b096-4cec-86c9-2cbddaad8e74
O'Neill, Jason W.
1abf1e09-b5d7-499f-9d2f-1d20d1007142
Dallman, Claire L.
d0b9f211-1d21-4b5e-bd25-ec9dd56492fe
Mouzakiti, Amalia
b90571cd-47a7-4156-b69b-ec0bf0e17106
Habens, Fay
3e4cce4b-4521-4702-9582-f817d25aad37
Brimmell, Matthew
4bb675a5-c3f0-4ddb-ae49-d39257ba79e1
Zhang, Kam Y.G.
d4816828-fe84-462a-bf8a-c1f0df2c4158
Craig, Ruth W.
3449fcc5-3f49-406d-8b65-650b53b11784
Marcusson, Eric G.
905194c7-075f-4089-aedf-ccd4e5f8e0e2
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Michels, J., O'Neill, Jason W., Dallman, Claire L., Mouzakiti, Amalia, Habens, Fay, Brimmell, Matthew, Zhang, Kam Y.G., Craig, Ruth W., Marcusson, Eric G., Johnson, Peter W.M. and Packham, Graham (2004) Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene, 23 (28), 4818-4827. (doi:10.1038/sj.onc.1207648).

Record type: Article

Abstract

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.

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More information

Published date: 17 June 2004
Keywords: apoptosis, Mcl-1, antisense, non-hodgkin's lymphoma, Bcl-2, caspase

Identifiers

Local EPrints ID: 26481
URI: http://eprints.soton.ac.uk/id/eprint/26481
ISSN: 0950-9232
PURE UUID: 402f171c-c3ae-481b-b342-45f23776153b
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

Catalogue record

Date deposited: 12 Apr 2006
Last modified: 16 Mar 2024 03:14

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Contributors

Author: J. Michels
Author: Jason W. O'Neill
Author: Claire L. Dallman
Author: Amalia Mouzakiti
Author: Fay Habens
Author: Matthew Brimmell
Author: Kam Y.G. Zhang
Author: Ruth W. Craig
Author: Eric G. Marcusson
Author: Graham Packham ORCID iD

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