Journal
BIOCHEMICAL JOURNAL
Volume 426, Issue -, Pages 293-306Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20091459
Keywords
mitogen-activated protein kinase kinase-1 (MEK-1); mRNA stability; ornithine decarboxylase; polyamine; ribonucleoprotein; translational regulation; 3 '-untranslated region (3 '-UTR)
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Funding
- Department of Veterans Affairs, U.S.A.
- National Institutes of Health [DK-57819, DK-61972, DK-68461]
- National Institute on Aging
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MEK-1 [MAPK (mitogen-activated protein kinase) kinase-1] is all important signal transducing enzyme that is implicated ill 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 Mill 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 vas silenced. These results indicate that polyamines destabilize the Mill 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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