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J. Biol. Chem., Vol. 279, Issue 21, 21724-21731, May 21, 2004

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A Cellular UDP-glucose Deficiency Causes Overexpression of Glucose/Oxygen-regulated Proteins Independent of the Endoplasmic Reticulum Stress Elements^*

Marietta Flores-Diaz, Juan-Carlos Higuita¶, Inger Florin, Tetsuya Okada||, Piero Pollesello**, Tomas Bergman, Monica Thelestam, Kazutoshi Mori, and Alberto Alape-Giron¶¶||||

From the Microbiology and Tumorbiology Center and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden, the Instituto Clodomiro Picado, Facultad de Microbología and ^¶¶Departamento de Bioquímica, Facultad de Medicina, Universidad de Costa Rica, San Jose 2060, Costa Rica, the ^||Graduate School of Biostudies, Kyoto University, Kyoto 606-8304, Japan, the Department of Biophysics, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake, Sakyo-ku, Kyoto 606-8502, Japan, and ^**Orion-Pharma, R&D, Drug Design Unit, NMR Laboratory, P. O. Box 65, FIN-02101 Espoo, Finland

A low level of UDP-Glc occurs in cells exposed to hypoxia or glucose starvation. This work reveals that a 65% reduction in the cellular UDP-Glc level causes up-regulation of the mitochondrial chaperone GRP75 and the endoplasmic reticulum (ER) resident chaperones GRP58, ERp72, GRP78, GRP94, GRP170, and calreticulin. Conditions that cause misfolding of proteins within the ER activate the transcription factors ATF6/ and induce translation of the transcription factors XBP-1/TREB5 and ATF4/CREB2. These transcription factors induce the overexpression of ER chaperones and CHOP/GADD153. However, the 65% decrease in the cellular UDP-Glc level does not cause activation of ATF6, splicing of XBP-1/TREB5, induction of ATF4/CREB2, or expression of CHOP/GADD153. The activity of the promoters of the ER chaperones is increased in UDP-Glcdeficient cells, but the activity of the CHOP/GADD153 promoter is not affected, in comparison with their respective activities in cells having compensated for the UDP-Glc deficiency. The results demonstrate that the unfolded protein response remains functionally intact in cells with a 65% decrease in the cellular UDP-Glc level and provide evidence that this decrease is a stress signal in mammalian cells, which triggers the coordinate overexpression of mitochondrial and ER chaperones, independently of the ER stress elements.

Received for publication, November 24, 2003 , and in revised form, March 5, 2004.

^* This work was supported in part by Swedish Cancer Society Grants 3826 and 1806, Fundación CR-USA Grant 1302-CT, Vicerrectoría de Investigación de la Universidad de Costa Rica Grant 741-A3-503, Swedish Medical Research Council Grants 16X-05969 and 03X-10832, the Ministry of Education, Culture, Sports, Science and Technology of Japan Grant 15GS0310, and Magnus Bergvall Foundation and Karolinska Institutet Research Funds. 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.

^¶ Recipient of a fellowship from the Instituto Colombiano para el desarrollo de la ciencia y la tecnologia (Colciencias).

^|||| To whom correspondence should be addressed. Tel.: 506-22-93-135 or 506-22-90-344; Fax: 506-29-20-485; E-mail: aalape{at}cariari.ucr.ac.cr.

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