Beta-catenin regulates the gene of MMP-26, a novel metalloproteinase expressed both in carcinomas and normal epithelial cells.
There are several unorthodox features, which distinguish the non-redundant and unique novel matrix metalloproteinase-26 (MMP-26) (an enzyme that has recently evolved and does not exist in rodents but is present in humans) from other members of the MMP superfamily. This report describes our recent efforts to gain a better understanding of the mechanisms which restrict expression of MMP-26 to certain cell/tissue types. We examined transcriptional regulation of the human MMP-26 gene in normal and malignant cells. The AP-1 and Tcf-4 sites of the MMP-26 promoter appear most potent in regulating the expression of the MMP-26-luciferase chimera in HEK293 embryonic kidney and MCF7 breast carcinoma cells. Key regulators of the Wnt pathway (beta-catenin and lymphoid enhancer-binding factor/T-cell factor with which beta-catenin associates) enhanced the transcriptional activity of MMP-26 suggesting that the MMP-26 gene is a likely target of the Wnt pathway. Immunostaining, gene arrays and reverse-transcriptase polymerase chain reaction (RT-PCR) confirm the presence of MMP-26 in normal cells, including the apical epithelial conjunctiva cells of the human eye, as well as in malignant cells of epithelial origin. MMP-26 predominantly accumulates in its proenzyme form in the intracellular milieu of the transfected breast carcinoma MCF7 cells. This study brings us a step forward towards a better understanding of the unconventional role, regulation and functions of epithelial cell MMP-26 in physiological conditions and in neoplasms.
Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92093, USA.
Natalia D
ND
Marchenko
George N
GN
Marchenko
Robert N
RN
Weinreb
James D
JD
Lindsey
Ainura
A
Kyshtoobayeva
Howard C
HC
Crawford
Alex Y
AY
Strongin
D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D007120:Immunochemistry; D008156:Luciferases / Q000032:analysis; D051821:Lymphoid Enhancer-Binding Factor 1; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012590:Sclera / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D008156:Luciferases; C410599:MMP26 protein, human; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted; D018631:ras Proteins