Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin.
A novel matrix metalloproteinase-26 (MMP-26) is known to be specifically expressed in epithelial carcinomas. To facilitate studies of MMP-26 transcriptional regulation, we have cloned and characterized a 1 kb 5'-flanking region of the human MMP-26 gene. Altogether, our findings indicate that the MMP-26 promoter has distinctive structural and functional features among MMP genes. An unusual polyadenylation site proximal to the transcription-factor-binding sites protects transcription of the MMP-26 gene from the upstream promoters and represents a part of the stringent transcriptional regulation of the gene. The MMP-26 gene has a consensus TATA-box and one transcriptional start site located 60 and 35 nucleotides upstream of the translational start site, respectively. The MMP-26 promoter was able to drive luciferase expression in human A549 lung carcinoma, HT1080 fibrosarcoma and HEK293 embryonic kidney cells. The basal transcription efficiency of the MMP-26 promoter is relatively low, thereby explaining the minute expression of the gene in most cells and tissues. When compared with other MMP genes, the MMP-26 promoter contains binding sites for a few transcription factors. Sequential deletion and mutation analysis, and electrophoretic mobility-shift assay have identified the T-cell factor-4 (Tcf-4) motif and the activator protein-1 site as the major regulatory elements of the MMP-26 promoter. Since previous studies have established that the Tcf-4 transcription factor is subjected exclusively to regulation through the beta-catenin/E(epithelial)-cadherin pathway, this implies the specific expression of MMP-26 in cancer cells of epithelial origin.
Marchenko
George N
GN
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
Marchenko
Natalia D
ND
Leng
Jay
J
Strongin
Alex Y
AY
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002678:Chimera / Q000235:genetics; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005809:Genes, Regulator; D006801:Humans; D008156:Luciferases / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics*; D053505:Matrix Metalloproteinases, Secreted; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D008156:Luciferases; C410599:MMP26 protein, human; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted