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J. Biol. Chem., Vol. 281, Issue 36, 26089-26101, September 8, 2006

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Translational Control of Collagen Prolyl 4-Hydroxylase-(I) Gene Expression under Hypoxia^*

Michael Fähling¹, Ralf Mrowka, Andreas Steege, Grit Nebrich^¶, Andrea Perlewitz, Pontus B. Persson, and Bernd J. Thiele

From the Charité, Universitätsmedizin Berlin, Institut für Vegetative Physiologie, D-10117 Berlin, Germany, the Freie Universität Berlin, Institut für Biologie, D-14195 Berlin, Germany, and the ^¶Charité, Universitätsmedizin Berlin, Institut für Humangenetik, D-13353 Berlin, Germany

Hypoxia is a pro-fibrotic stimulus, which is associated with enhanced collagen synthesis, as well as with augmented collagen prolyl 4-hydroxylase (C-P4H) activity. C-P4H activity is controlled mainly by regulated expression of the C-P4H subunit. In this study we demonstrate that the increased synthesis of C-P4H-(I) protein in human HT1080 fibroblasts under long term hypoxia (36 h, 1% oxygen) is controlled at the translational level. This is mediated by an interaction of RNA-binding protein nucleolin (64 kDa form) at the 5'- and 3'-untranslated regions (UTR) of the mRNA. The 5'/3'-UTR-dependent mechanism elevates the C-P4H-(I) expression rate 2.3-fold, and participates in a 5.3-fold increased protein level under long term hypoxia. The interaction of nucleolin at the 5'-UTR occurs directly and depends on the existence of an AU-rich element. Statistical evaluation of the 64-kDa nucleolin/RNA interaction studies revealed a core binding sequence, corresponding to UAAAUC or AAAUCU. At the 3'-UTR, nucleolin assembles indirectly via protein/protein interaction, with the help of another 3'-UTR-binding protein, presumably annexin A2. The increased protein level of the 64-kDa nucleolin under hypoxia can be attributed to an autocatalytic cleavage of a high molecular weight nucleolin form, without alterations in nucleolin mRNA concentration. Thus, the alteration of translational efficiency by nucleolin, which occurs through a hypoxia inducible factor independent pathway, is an important step in C-P4H-(I) regulation under hypoxia.

Received for publication, May 23, 2006 , and in revised form, July 10, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants GRK754 and TH459/5 and the Bundesministerium für Bildung und Forschung (BMBF), Core Facility Proteomics (Charité, Universitätsmedizin Berlin). 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.

¹ To whom correspondence should be addressed: Tucholskystr. 2, D-10117 Berlin, Germany. Tel.: 49-30-450-528268; Fax: 49-30-450-528972; E-mail: michael.faehling{at}charite.de.

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