MEK-1 [MAPK (mitogen-activated protein kinase) kinase-1] is an important signal transducing enzyme that is implicated in many aspects of cellular functions. In the present paper, we report that cellular polyamines regulate MEK-1 expression at the post-transcriptional level through the RNA-binding protein HuR (Hu-antigen R) in IECs (intestinal epithelial cells). Decreasing the levels of cellular polyamines by inhibiting ODC (ornithine decarboxylase) stabilized MEK-1 mRNA and promoted its translation through enhancement of the interaction between HuR and the 3′-untranslated region of MEK-1 mRNA, whereas increasing polyamine levels by ectopic ODC overexpression destabilized the MEK-1 transcript and repressed its translation by reducing the abundance of HuR–MEK-1 mRNA complex; neither intervention changed MEK-1 gene transcription via its promoter. HuR silencing rendered the MEK-1 mRNA unstable and inhibited its translation, thus preventing increases in MEK-1 mRNA and protein in polyamine-deficient cells. Conversely, HuR overexpression increased MEK-1 mRNA stability and promoted its translation. Inhibition of MEK-1 expression by MEK-1 silencing or HuR silencing prevented the increased resistance of polyamine-deficient cells to apoptosis. Moreover, HuR overexpression did not protect against apoptosis if MEK-1 expression was silenced. These results indicate that polyamines destabilize the MEK-1 mRNA and repress its translation by inhibiting the association between HuR and the MEK-1 transcript. Our findings indicate that MEK-1 is a key effector of the HuR-elicited anti-apoptotic programme in IECs.
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Research Article|
February 24 2010
Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal epithelial apoptosis
Peng-Yuan Wang;
Peng-Yuan Wang
1
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Jaladanki N. Rao;
Jaladanki N. Rao
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Tongtong Zou;
Tongtong Zou
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Lan Liu;
Lan Liu
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Lan Xiao;
Lan Xiao
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
‡Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
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Ting-Xi Yu;
Ting-Xi Yu
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Douglas J. Turner;
Douglas J. Turner
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Myriam Gorospe;
Myriam Gorospe
§Laboratory of Cellular and Molecular Biology, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, U.S.A.
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Jian-Ying Wang
Jian-Ying Wang
2
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
‡Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
2To whom correspondence should be addressed (email jwang@smail.umaryland.edu).
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Publisher: Portland Press Ltd
Received:
September 16 2009
Revision Received:
December 06 2009
Accepted:
December 14 2009
Accepted Manuscript online:
December 14 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 426 (3): 293–306.
Article history
Received:
September 16 2009
Revision Received:
December 06 2009
Accepted:
December 14 2009
Accepted Manuscript online:
December 14 2009
Citation
Peng-Yuan Wang, Jaladanki N. Rao, Tongtong Zou, Lan Liu, Lan Xiao, Ting-Xi Yu, Douglas J. Turner, Myriam Gorospe, Jian-Ying Wang; Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal epithelial apoptosis. Biochem J 15 March 2010; 426 (3): 293–306. doi: https://doi.org/10.1042/BJ20091459
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