Alternative splicing and promoter usage generates an intracellular stromelysin 3 isoform directly translated as an active matrix metalloproteinase.
Human stromelysin 3 (ST3) is a matrix metalloproteinase (MMP) that has been implicated in cancer progression and in various tissue remodeling processes. Unlike most MMPs, ST3 is characterized by a distinct substrate specificity and a specific regulation and is not directly involved in extracellular matrix degradation. In the present study, we have identified an additional ST3 gene promoter that is accessible to nuclear factors such as C/EBP and retinoic acid receptors. This human specific promoter is inducible and controls the expression of a novel ST3 transcript called the beta-ST3 that is expressed in cultured cells and in placenta. This transcript encodes a 40-kDa ST3 isoform that lacks both the signal peptide common to all secreted MMPs and the prodomain that normally maintains enzyme latency. Consistent with the lack of a signal peptide, the beta-ST3 was found to be intracellular. The relative amount of the extracellular alpha-ST3 isoform was about 20-fold higher than that of the intracellular ST3 isoforms, as estimated by Western blot analysis. Furthermore, recombinant beta-ST3 produced in Escherichia coli exhibits a proteolytic activity against alpha1-proteinase inhibitor, a substrate previously shown to be inactivated by the alpha-ST3. Therefore, although it was thought that all MMPs were synthesized as inactive zymogens and functioned extracellularly, this is the first MMP isoform reported that is generated by alternative promoter usage and directly translated as an active enzyme. Although the intracellular function of the beta-ST3 remains to be investigated, these data support the idea that the functions of MMPs are not restricted to the extracellular space.
Luo
Daochun
D
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U184, CNRS, Université Louis Pasteur, BP 10142, 67404 Illkirch cedex, Communauté Urbaine de Strasbourg, France.
Mari
Bernard
B
Stoll
Isabelle
I
Anglard
Patrick
P
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D018076:DNA, Complementary; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D007527:Isoenzymes; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases