Mcl-1 (myeloid cell leukaemia-1) is a Bcl-2 family member with short-term pro-survival functions but whose other functions, demonstrated by embryonic lethality of knockout mice, do not involve apoptosis. In the present study, we show a cell-cycle-regulatory role of Mcl-1 involving a shortened form of the Mcl-1 polypeptide, primarily localized to the nucleus, which we call snMcl-1. snMcl-1 interacts with the cell-cycle-regulatory protein Cdk1 (cyclin-dependent kinase 1; also known as cdc2) in the nucleus, and Cdk1 bound to snMcl-1 was found to have a lower kinase activity. The interaction with Cdk1 occurs in the absence of its cyclin partners and is enhanced on treatment of cells with G2/M blocking agents, but not by G1/S blocking. The snMcl-1 polypeptide is present during S and G2 phases and is negligible in G1. Overexpression of human Mcl-1 in a murine myeloid progenitor cell line resulted in a lower rate of proliferation. Furthermore, Mcl-1-overexpressing cells had lower total Cdk1 kinase activity compared with parental cells, in both anti-Cdk1 and anti-cyclin B1 immunoprecipitates. The latter results suggest that binding to snMcl-1 alters the ability of Cdk1 to bind its conventional partner, cyclin B1. Given the important role of Cdk1 in progression through G2 and M phases, it is probable that the inhibition of Cdk1 activity accounts for the inhibitory effect of Mcl-1 on cell growth.
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Research Article|
April 26 2005
A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1
Sarwat JAMIL;
Sarwat JAMIL
*Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6
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Rafat SOBOUTI;
Rafat SOBOUTI
*Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6
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Payman HOJABRPOUR;
Payman HOJABRPOUR
*Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6
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Meera RAJ;
Meera RAJ
*Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6
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Juergen KAST;
Juergen KAST
†Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada V6H 3Z6
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Vincent DURONIO
Vincent DURONIO
1
*Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, 2660 Oak St., Vancouver, BC, Canada V6H 3Z6
1To whom correspondence should be addressed (email vduronio@interchange.ubc.ca).
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Publisher: Portland Press Ltd
Received:
September 16 2004
Revision Received:
November 03 2004
Accepted:
November 22 2004
Accepted Manuscript online:
November 22 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 387 (3): 659–667.
Article history
Received:
September 16 2004
Revision Received:
November 03 2004
Accepted:
November 22 2004
Accepted Manuscript online:
November 22 2004
Citation
Sarwat JAMIL, Rafat SOBOUTI, Payman HOJABRPOUR, Meera RAJ, Juergen KAST, Vincent DURONIO; A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1. Biochem J 1 May 2005; 387 (3): 659–667. doi: https://doi.org/10.1042/BJ20041596
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