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Originally published In Press as doi:10.1074/jbc.M108359200 on November 1, 2001

J. Biol. Chem., Vol. 277, Issue 2, 1560-1567, January 11, 2002
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NM23-H1 and NM23-H2 Repress Transcriptional Activities of Nuclease-hypersensitive Elements in the Platelet-derived Growth Factor-A Promoter*

Deqin MaDagger §, Zhenlan XingDagger §, Bin LiuDagger §||, Nancy G. PedigoDagger , Stephen G. Zimmer**, Zengliang Bai, Edith H. PostelDagger Dagger , and David M. KaetzelDagger §§

From the Departments of Dagger  Molecular and Biomedical Pharmacology and ** Microbiology and Immunology, University of Kentucky Medical Center, Lexington, Kentucky 40536, the Dagger Dagger  Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, and the  Department of Developmental Biology, Shandong University, Jinan 250100, Peoples Republic of China

The platelet-derived growth factor (PDGF)-A promoter is regulated by a number of GC-rich regulatory elements that possess non-B-form DNA structures. Screening of a HeLa cDNA expression library with the C-rich strand of a PDGF-A silencer sequence (5'-S1 nuclease-hypersensitive site (SHS)) yielded three cDNA clones encoding NM23-H1, a protein implicated as a suppressor of metastasis in melanoma and breast carcinoma. Recombinant human NM23-H1 cleaved within the 3'-portions of both 5'-SHS strands in either single-stranded or duplex forms. In contrast, NM23-H2, known as a transcriptional activator with a DNA cleavage function, cleaved within the 5'-portions of both strands, revealing that NM23-H1 and NM23-H2 cleave at distinct sites of the 5'-SHS and by different mechanisms. NM23-H1 and NM23-H2 also cleaved within the PDGF-A basal promoter region, again exhibiting preferences for cleavage within the 5'- and 3'-portions of the element, respectively. Transient transfection analyses in HepG2 cells revealed that both NM23-H1 and -H2 repressed transcriptional activity driven by the PDGF-A basal promoter (-82 to +8). Activity of the negative regulatory region (-1853 to -883), which contains the 5'-SHS, was also inhibited modestly by NM23-H1 and NM23-H2. These studies demonstrate for the first time that NM23-H1 interacts both structurally and functionally with DNA. They also indicate a role for NM23 proteins in repressing transcription of a growth factor oncogene, providing a possible molecular mechanism to explain their metastasis-suppressing effects.

* This work was supported by Grants R01-CA83237 (to D. M. K.) and R01-CA76496 (to E. H. P.) from the NCI, National Institutes of Health, Grant R29-DK45518 (to D. M. K.) from the NIDDK, National Institutes of Health, and funds from the L. P. Markey Cancer Center/McDowell Foundation (to S. Z.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| Present address: Div. of Hematology and Oncology, School of Medicine, University of California, Los Angeles, CA 90095-1678.

§§ To whom correspondence should be addressed: Dept. of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, MS305, 800 Rose St., Lexington, KY 40536. Tel.: 859-257-6558; Fax: 859-323-1981; E-mail: dmkaetz@pop.uky.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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