RGD Reference Report - Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). - Rat Genome Database

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Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1).

Authors: Cheng, S  Alfonso-Jaume, MA  Mertens, PR  Lovett, DH 
Citation: Cheng S, etal., Biochem J 2002 Sep 15;366(Pt 3):807-16.
RGD ID: 633207
Pubmed: PMID:12010125   (View Abstract at PubMed)
PMCID: PMC1222814   (View Article at PubMed Central)
DOI: DOI:10.1042/BJ20020202   (Journal Full-text)

Gelatinase A transcriptional regulation is the consequence of combinatorial interactions with key promoter and enhancer elements identified within this gene. A potent 40 bp 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 17 kDa RE-1-binding protein as the rat homologue (nm23-beta) of the human nm23-H1 metastasis suppressor gene. Recombinant nm23-beta protein bound only the single-stranded forms of the RE-1 sequence. Mutagenesis revealed direct interaction of nm23-beta 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-beta protein competed for single-stranded YB-1 binding. Transient transfection of MC with an nm23-beta 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-beta repression was demonstrated within the context of the RE-1/homologous gelatinase A promoter. Co-transfection of nm23-beta blocked YB-1-mediated activation of transcription and expression of gelatinase A. Nm23-beta 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-beta (or the human nm23-H1) may be a component of the reduced metastatic capabilities of cells expressing high levels of this protein.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of gene expression  IDA 633207Mmp2RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
RNA polymerase II transcription regulatory region sequence-specific DNA binding  IDA 633207 RGD 
single-stranded DNA binding  IDA 633207 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Nme1  (NME/NM23 nucleoside diphosphate kinase 1)

Objects referenced in this article
Gene Mmp2 matrix metallopeptidase 2 Rattus norvegicus
Gene Ybx1 Y box binding protein 1 Rattus norvegicus

Additional Information