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J. Biol. Chem., Vol. 278, Issue 33, 30624-30633, August 15, 2003

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Repression of the Human Adenine Nucleotide Translocase-2 Gene in Growth-arrested Human Diploid Cells

THE ROLE OF NUCLEAR FACTOR-1^*

Katarina Luciakova   ¶ ||, Peter Barath   ¶, Daniela Poliakova  , Annika Persson ** and B. Dean Nelson 

From the Departments of Biochemistry and Biophysics and ^**Cell Biology, Arrhenius Laboratories, Stockholm University, S-106 91 Stockholm, Sweden and the Cancer Research Institute, Slovak Academy of Sciences, 833 91 Bratislava, Slovak Republic

Adenine nucleotide translocase-2 (ANT2) catalyzes the exchange of ATP for ADP across the mitochondrial membrane, thus playing an important role in maintaining the cytosolic phosphorylation potential required for cell growth. Expression of ANT2 is activated by growth stimulation of quiescent cells and is down-regulated when cells become growth-arrested. In this study, we address the mechanism of growth arrest repression. Using a combination of transfection, in vivo dimethyl sulfate mapping, and in vitro DNase I mapping experiments, we identified two protein-binding elements (Go-1 and Go-2) that are responsible for growth arrest of ANT2 expression in human diploid fibroblasts. Proteins that bound the Go elements were purified and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry as members of the NF1 family of transcription factors. Chromatin immunoprecipitation analysis showed that NF1 was bound to both Go-1 and Go-2 in quiescent human diploid cells in vivo, but not in the same cells stimulated to growth by serum. NF1 binding correlated with the disappearance of ANT2 transcripts in quiescent cells. Furthermore, overexpression of NF1-A, -C, and -X in NIH3T3 cells repressed expression of an ANT2-driven reporter gene construct. Two additional putative repressor elements in the ANT2 promoter, an Sp1 element juxtaposed to the transcription start site and a silencer centered at nucleotide –332, did not appear to contribute to growth arrest repression. Thus, enhanced binding of NF1 is a key step in the growth arrest repression of ANT2 transcription. To our knowledge, this is the first report showing a role for NF1 in growth arrest.

Received for publication, April 4, 2003 , and in revised form, May 23, 2003.

^* This work was supported by the Swedish Research Council and Slovak Science and Technology Assistance Agency (APVT) Agency Grant 26-002102 (to K. L.). 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.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Cancer Research Inst., Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava, Slovak Republic. Tel.: 421-2-5932-7109; Fax: 421-2-5932-7250; E-mail: Katarina.Luciakova{at}savba.sk.

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