The JNKs (c-Jun N-terminal kinases) are stress-activated serine/threonine kinases that can regulate both cell death and cell proliferation. We have developed a cell system to control JNK re-expression at physiological levels in JNK1/2-null MEFs (murine embryonic fibroblasts). JNK re-expression restored basal and stress-activated phosphorylation of the c-Jun transcription factor and attenuated cellular proliferation with increased cells in G1/S-phase of the cell cycle. To explore JNK actions to regulate cell proliferation, we evaluated a role for the cytosolic protein, STMN (stathmin)/Op18 (oncoprotein 18). STMN, up-regulated in a range of cancer types, plays a crucial role in the control of cell division through its regulation of microtubule dynamics of the mitotic spindle. In JNK1/2-null or c-Jun-null MEFs or cells treated with c-Jun siRNA (small interfering RNA), STMN levels were significantly increased. Furthermore, a requirement for JNK/cJun signalling was demonstrated by expression of wild-type c-Jun, but not a phosphorylation-defective c-Jun mutant, being sufficient to down-regulate STMN. Critically, shRNA (small hairpin RNA)-directed STMN down-regulation in JNK1/2-null MEFs attenuated proliferation. Thus JNK/c-Jun regulation of STMN levels provides a novel pathway in regulation of cell proliferation with important implications for understanding the actions of JNK as a physiological regulator of the cell cycle and tumour suppressor protein.
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Research Article|
August 13 2010
c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18
Yvonne Y. C. Yeap;
Yvonne Y. C. Yeap
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
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Ivan H. W. Ng;
Ivan H. W. Ng
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
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Bahareh Badrian;
Bahareh Badrian
†Lung Institute of Western Australia, Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, WA 6009, Australia
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Tuong-Vi Nguyen;
Tuong-Vi Nguyen
1
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
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Yan Y. Yip;
Yan Y. Yip
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
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Amardeep S. Dhillon;
Amardeep S. Dhillon
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
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Steven E. Mutsaers;
Steven E. Mutsaers
†Lung Institute of Western Australia, Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, WA 6009, Australia
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John Silke;
John Silke
‡Department of Biochemistry, La Trobe University, VIC 3083, Australia
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Marie A. Bogoyevitch;
Marie A. Bogoyevitch
2
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
2Correspondence may be addressed to either of these authors (email marieb@unimelb.edu.au or ngd@unimelb.edu.au).
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Dominic C. H. Ng
Dominic C. H. Ng
2
*Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC 3010, Australia
2Correspondence may be addressed to either of these authors (email marieb@unimelb.edu.au or ngd@unimelb.edu.au).
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Publisher: Portland Press Ltd
Received:
March 23 2010
Revision Received:
June 25 2010
Accepted:
July 01 2010
Accepted Manuscript online:
July 01 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 430 (2): 345–354.
Article history
Received:
March 23 2010
Revision Received:
June 25 2010
Accepted:
July 01 2010
Accepted Manuscript online:
July 01 2010
Citation
Yvonne Y. C. Yeap, Ivan H. W. Ng, Bahareh Badrian, Tuong-Vi Nguyen, Yan Y. Yip, Amardeep S. Dhillon, Steven E. Mutsaers, John Silke, Marie A. Bogoyevitch, Dominic C. H. Ng; c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18. Biochem J 1 September 2010; 430 (2): 345–354. doi: https://doi.org/10.1042/BJ20100425
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