Gelatinase A transcriptional regulation is the consequence of combinatorial interactions with key promoter and enhancer elements identified within this gene. A potent 40bp enhancer response element, RE-1, located in the near 5′ flanking regions of the rat and human gelatinase A genes drives high-level expression in glomerular mesangial cells (MCs). Southwestern-blot analysis of MC nuclear extracts revealed specific interactions of RE-1 with at least four proteins, of which three have been identified as p53, activator protein 2 and the single-stranded DNA-binding factor Y-box protein-1 (YB-1). In the present study, we report the identification of a fourth 17kDa RE-1-binding protein as the rat homologue (nm23-β) of the human nm23-H1 metastasis suppressor gene. Recombinant nm23-β protein bound only the single-stranded forms of the RE-1 sequence. Mutagenesis revealed direct interaction of nm23-β with a repeat sequence, 5′-GGGTTT-3′, shown previously to specifically interact with YB-1 [Mertens, Harendza, Pollock and Lovett (1997) J. Biol. Chem. 272, 22905—22912], and recombinant nm23-β protein competed for single-stranded YB-1 binding. Transient transfection of MC with an nm23-β expression plasmid within the context of a RE-1/simian virus 40 promoter/luciferase reporter yielded a concentration-dependent repression (80—90%) of luciferase activity in MC and Rat1 fibroblasts. A similar pattern of nm23-β repression was demonstrated within the context of the RE-1/homologous gelatinase A promoter. Co-transfection of nm23-β blocked YB-1-mediated activation of transcription and expression of gelatinase A. Nm23-β may be an important physiological regulator of gelatinase A transcription that acts by competitive interference with the single-stranded transactivator YB-1. Gelatinase A is a key mediator of tumour metastasis, suggesting that competitive suppression of transcription by nm23-β (or the human nm23-H1) may be a component of the reduced metastatic capabilities of cells expressing high levels of this protein.
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September 2002
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Research Article|
September 15 2002
Tumour metastasis suppressor, nm23-β, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1)
Sunfa CHENG;
Sunfa CHENG
1
∗Department of Medicine, San Francisco Veterans Affair Medical Center, University of California, 4150 Clement Street, San Francisco, CA 94121, U.S.A.,
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Maria Alexandra ALFONSO-JAUME;
Maria Alexandra ALFONSO-JAUME
1
∗Department of Medicine, San Francisco Veterans Affair Medical Center, University of California, 4150 Clement Street, San Francisco, CA 94121, U.S.A.,
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Peter R. MERTENS;
Peter R. MERTENS
†Medical Clinic II, Rheinisch Westfaelische Technische Hochschule Aachen, Pauwelsstrasse 30, D-52057, Aachen, Germany
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David H. LOVETT
David H. LOVETT
2
∗Department of Medicine, San Francisco Veterans Affair Medical Center, University of California, 4150 Clement Street, San Francisco, CA 94121, U.S.A.,
2To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
January 31 2002
Revision Received:
April 23 2002
Accepted:
May 15 2002
Accepted Manuscript online:
May 15 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (3): 807–816.
Article history
Received:
January 31 2002
Revision Received:
April 23 2002
Accepted:
May 15 2002
Accepted Manuscript online:
May 15 2002
Citation
Sunfa CHENG, Maria Alexandra ALFONSO-JAUME, Peter R. MERTENS, David H. LOVETT; Tumour metastasis suppressor, nm23-β, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). Biochem J 15 September 2002; 366 (3): 807–816. doi: https://doi.org/10.1042/bj20020202
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