The Expression of Matrix Metalloprotease 20 is Stimulated by Wild Type but not by 4 bp- or 2 bp- Deletion Mutant DLX3
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Mutations in DLX3 are associated with both autosomal dominant hypoplastic hypomaturation amelogenesis imperfecta (ADHHAI) and tricho-dento-osseous (TDO) syndrome. ADHHAI is caused by a c.561_562delCT (2bpdel DLX3) mutation whereas TDO syndrome is associated with a c.571_574delGGGG (4bp-del DLX3) mutation. However, although the causal relationships between DLX3 and an enamel phenotype have been established, the pathophysiological role of DLX3 mutations in enamel development has not yet been clarified. In our current study, we prepared expression vectors for wild type and deletion mutant DLX3 products (4bp-del DLX3, 2bp-del DLX3) and examined the effects of their overexpression on the expression of the enamel matrix proteins and proteases. Wild type DLX3 enhanced the expression of matrix metalloprotease 20 (MMP20) mRNA and protein in murine ameloblast-like cells. However, neither a 4bp-del nor 2bpdel DLX3 increased MMP20 expression. Wild type DLX3, but not the above DLX3 mutants, also increased the activity of reporters containing 1.5 kb or 0.5 kb of the MMP20 promoter. An examination of protein stability showed that the half-life of wild type DLX3 protein was less than 12 h whilst that of both deletion mutants was longer than 24 h. Endogenous Dlx3 was also found to be continuously expressed during ameloblast differentiation. Since inactivating mutations in the gene encoding MMP20 are associated with amelogenesis imperfecta, the inability of 4bp-del or 2bp-del DLX3 to induce MMP20 expression suggests a possible involvement of such mutations in the enamel phenotype associated with TDO syndrome or ADHHAI.
Abstract
Mutations in DLX3 are associated with both autosomal dominant hypoplastic hypomaturation amelogenesis imperfecta (ADHHAI) and tricho-dento-osseous (TDO) syndrome. ADHHAI is caused by a c.561_562delCT (2bpdel DLX3) mutation whereas TDO syndrome is associated with a c.571_574delGGGG (4bp-del DLX3) mutation. However, although the causal relationships between DLX3 and an enamel phenotype have been established, the pathophysiological role of DLX3 mutations in enamel development has not yet been clarified. In our current study, we prepared expression vectors for wild type and deletion mutant DLX3 products (4bp-del DLX3, 2bp-del DLX3) and examined the effects of their overexpression on the expression of the enamel matrix proteins and proteases. Wild type DLX3 enhanced the expression of matrix metalloprotease 20 (MMP20) mRNA and protein in murine ameloblast-like cells. However, neither a 4bp-del nor 2bpdel DLX3 increased MMP20 expression. Wild type DLX3, but not the above DLX3 mutants, also increased the activity of reporters containing 1.5 kb or 0.5 kb of the MMP20 promoter. An examination of protein stability showed that the half-life of wild type DLX3 protein was less than 12 h whilst that of both deletion mutants was longer than 24 h. Endogenous Dlx3 was also found to be continuously expressed during ameloblast differentiation. Since inactivating mutations in the gene encoding MMP20 are associated with amelogenesis imperfecta, the inability of 4bp-del or 2bp-del DLX3 to induce MMP20 expression suggests a possible involvement of such mutations in the enamel phenotype associated with TDO syndrome or ADHHAI.
참고문헌 (27)
- Bartlett JD, "A developmental comparison of matrix metalloproteinase-20 and amelogenin null mouse enamel", Eur J Oral Sci, 114(1), pp.18~23 (2006)
- 차지훈, "Dlx3 plays a role as a positive regulator of osteoclast differentiation", International Journal of Oral Biology, 32(3), pp.85~91 (2007), 대한구강생물학회
- Choi SJ, "A 4 bp deletion mutation in DLX3 enhances osteoblastic differentiation and bone formation in vitro", Bone, 42, pp.162~171 (2008)
- Diamond E, "Functional interactions between Dlx2 and lymphoid enhancer factor regulate Msx2", Nucleic Acids Res, 34, pp.5951~5965 (2006)
- Dong J, "DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism", Am J Med Genet A, 133A, pp.138~141 (2005)
- Du C, "Supramolecular assembly of amelogenin nanospheres into birefringent microribbons", Science, 307, pp.1450~1454 (2005)
- Duverger O, "Molecular consequences of a frameshifted DLX3 mutant leading to Tricho-Dento-Osseous syndrome", J Biol Chem, 283, pp.20198~20208 (2008)
- Ezashi T, "The role of homeobox protein distal-less 3 and its interaction with ETS2 in regulating bovine interferon-tau gene expression - synergistic transcriptional activation with ETS2", Biol Reprod, 79, pp.115~124 (2008)
- Feledy JA, "Transcriptional activation by the homeodomain protein distal-less 3", Nucleic Acids Res, 27, pp.764~770 (1999)
- Fincham AG, "Self-assembly of a recombinant amelogenin protein generates supramolecular structures", J Struct Biol, 112, pp.103~109 (1994)
- Fincham AG, "The structural biology of the developing dental enamel matrix", J Struct Biol, 126, pp.270~299 (1999)
- Ghoul-Mazgar S, "Expression pattern of Dlx3 during cell differentiation in mineralized tissues", Bone, 37, pp.799~809 (2005)
- Hunter GK, "Effects of recombinant amelogenin on hydroxyapatite formation in vitro", Calcif Tissue Int, 65, pp.226~231 (1999)
- Lézot F, "Physiological implications of DLX homeoproteins in enamel formation", J Cell Physiol, 216, pp.688~697 (2008)
- Lu Y, "Functions of KLK4 and MMP-20 in dental enamel formation", Biol Chem, 389, pp.695~700 (2008)
- Margolis HC, "Role of macromolecular assembly of enamel matrix proteins in enamel formation", J Dent Res, 85, pp.775~793 (2006)
- Morasso MI, "Placental failure in mice lacking the homeobox gene Dlx3", Proc Natl Acad Sci USA, 96, pp.162~167
- Nakata A, "Establishment and characterization of a spontaneously immortalized mouse ameloblast-lineage cell line", Biochem Biophys Res Commun, 308, pp.834~839 (2003)
- Park JC, "The amyloid protein APin is highly expressed during enamel mineralization and maturation in rat incisors", Eur J Oral Sci, 115, pp.153~160 (2007)
- Price JA, "Identification of a mutation in DLX3 associated with trichodento- osseous (TDO) syndrome", Hum Mol Genet, 7, pp.563~569 (1998)
- Price JA, "A common DLX3 gene mutation is responsible for trichodento- osseous syndrome in Virginia and North Carolina families", J Med Genet, 35, pp.825~828 (1998)
- Rechsteiner M, "PEST sequences and regulation by proteolysis", Trends Biochem Sci, 21, pp.267~271 (1996)
- Rogers S, "Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis", Science, 234, pp.364~368 (1986)
- Ryu OH, "Characterization of recombinant pig enamelysin activity and cleavage of recombinant pig and mouse amelogenins", J Dent Res, 78, pp.743~750 (1999)
- Wright JT, "The molecular etiologies and associated phenotypes of amelogenesis imperfecta", Am J Med Genet A, 140, pp.2547~2455 (2006)
- Wright JT, "DLX3 c.561_562delCT mutation causes attenuated phenotype of tricho-dento-osseous syndrome", Am J Med Genet A, 146, pp.343~349 (2008)
- Zhang Y, "JNK", c-Jun signaling pathway mediates the fluoride-induced downregulation of MMP-20 in vitro, 2007, pp.26, 633~641