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J. Biol. Chem., Vol. 279, Issue 50, 52007-52015, December 10, 2004

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Induction of CCAAT/Enhancer-binding Protein (C/EBP)-homologous Protein/Growth Arrest and DNA Damage-inducible Protein 153 Expression during Inhibition of Phosphatidylcholine Synthesis Is Mediated via Activation of a C/EBP-activating Transcription Factor-responsive Element^*

Michiel H. M. van der Sanden, Henriët Meems, Martin Houweling, J. Bernd Helms, and Arie B. Vaandrager

From the Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, and Institute of Biomembranes, University of Utrecht, P.O. Box 80176, Utrecht 3508 TD, The Netherlands

The gene for the proapoptotic transcription factor CCAAT/enhancer-binding protein (C/EBP)-homologous protein/growth arrest and DNA damage-inducible protein 153 (CHOP/GADD153) is induced by various cellular stresses. Previously, we described that inhibition of phosphatidylcholine (PC) synthesis in MT58 cells, which contain a temperature-sensitive mutation in CTP:phosphocholine cytidylyltransferase (CT), results in apoptosis preceded by the induction of CHOP. Here we report that prevention of CHOP induction, by expression of antisense CHOP, delays the PC depletion-induced apoptotic process. By mutational analysis of the conserved region in the promoter of the CHOP gene, we provide evidence that the C/EBP-ATF composite site, but not the ER stress-responsive element or the activator protein-1 site, is required for the increased expression of CHOP during PC depletion. Inhibition of PC synthesis in MT58 cells also led to an increase in phosphorylation of the stress-related transcription factor ATF2 and the stress kinase JNK after 8 and 16 h, respectively. In contrast, no phosphorylation of p38 MAPK was observed in MT58 cultured at the nonpermissive temperature. Treatment of MT58 cells with the JNK inhibitor SP600125 could rescue the cells from apoptosis but did not inhibit the phosphorylation of ATF2 or the induction of CHOP. Taken together, our results suggest that increased expression of CHOP during PC depletion depends on a C/EBP-ATF element in its promoter and might be mediated by binding of ATF2 to this element.

Received for publication, May 19, 2004 , and in revised form, September 29, 2004.

^* 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.

To whom correspondence should be addressed. Tel.: 31-30-2535378; Fax: 31-30-2535492; E-mail: A.B.Vaandrager{at}vet.uu.nl.

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