NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter

Deqin Ma; Zhenlan Xing; Bin Liu; Nancy G Pedigo; Stephen G Zimmer; Zengliang Bai; Edith H Postel; David M Kaetzel

doi:10.1074/jbc.M108359200

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NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter

Journal article

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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 Ma, Zhenlan Xing, Bin Liu, Nancy G Pedigo, Stephen G Zimmer, Zengliang Bai, Edith H Postel and David M Kaetzel

The Journal of biological chemistry, Vol.277(2), pp.1560-1567

01/11/2002

DOI: 10.1074/jbc.M108359200

PMID: 11694515

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Abstract

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.

Recombinant Proteins - metabolism

Promoter Regions, Genetic

Nucleoside-Diphosphate Kinase

Gene Library

Humans

Biomarkers, Tumor

Platelet-Derived Growth Factor - genetics

Transcription Factors - metabolism

Monomeric GTP-Binding Proteins - metabolism

Antigens, Neoplasm - metabolism

NM23 Nucleoside Diphosphate Kinases

Transcription, Genetic

HeLa Cells

Oligodeoxyribonucleotides - metabolism

Details

Title: Subtitle: NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter
Creators: Deqin Ma - Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA
Zhenlan Xing
Bin Liu
Nancy G Pedigo
Stephen G Zimmer
Zengliang Bai
Edith H Postel
David M Kaetzel
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.277(2), pp.1560-1567
DOI: 10.1074/jbc.M108359200
PMID: 11694515
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: R01-CA76496 / NCI NIH HHS R01-CA83237 / NCI NIH HHS R29-DK45518 / NIDDK NIH HHS
Language: English
Date published: 01/11/2002
Academic Unit: Pathology
Record Identifier: 9984047772102771

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