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J. Biol. Chem., Vol. 278, Issue 29, 27016-27023, July 18, 2003

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Increased AMP:ATP Ratio and AMP-activated Protein Kinase Activity during Cellular Senescence Linked to Reduced HuR Function^*

Wengong Wang , Xiaoling Yang , Isabel López de Silanes , David Carling  ¶ and Myriam Gorospe  ||

From the Laboratory of Cellular and Molecular Biology, NIA Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224 and the Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, London W12 0NN, United Kingdom

Cytoplasmic export of the RNA-binding protein HuR, a process that critically regulates its function, was recently shown to be inhibited by the AMP-activated protein kinase (AMPK). In the present investigation, treatment of human fibroblasts with AMPK activators such as 5-amino-imidazole-4-carboxamide riboside, antimycin A, and sodium azide inhibited cell growth and lowered the expression of proliferative genes. As anticipated, AMPK activation also decreased both the cytoplasmic HuR levels and the association of HuR with target radiolabeled transcripts encoding such proliferative genes. HuR function was previously shown to be implicated in the maintenance of a "young cell" phenotype in models of replicative cellular senescence. We therefore postulated that AMPK activation in human fibroblasts might contribute to the implementation of the senescence phenotype through mechanisms that included a reduction in HuR cytoplasmic presence. Indeed, AMP:ATP ratios were 2–3-fold higher in senescent fibroblasts compared with young fibroblasts. Accordingly, in vitro senescence was accompanied by a marked elevation in AMPK activity. Evidence that increased AMPK activity directly contributed to the implementation of the senescent phenotype was obtained through two experimental approaches. First, use of AMPK activators triggered senescence characteristics in fibroblasts, such as the acquisition of senescence-associated -galactosidase (-gal) activity and increased p16^INK4a expression. Second, infection of cells with an adenoviral vector that expresses active AMPK increased senescence-associated -gal activity, whereas infection with an adenovirus that expresses dominant-negative AMPK decreased senescence-associated -gal activity. Together, our results indicate that AMPK activation can cause premature fibroblast senescence through mechanisms that likely involve reduced HuR function.

Received for publication, January 10, 2003 , and in revised form, April 14, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by the Medical Research Council (UK).

^|| To whom correspondence should be addressed: Box 12, LCMB, NIA-IRP, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Tel.: 410-558-8443; Fax: 410-558-8386; E-mail: myriam-gorospe{at}nih.gov.

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