MMP28 gene expression is regulated by Sp1 transcription factor acetylation.
MMP-28 (epilysin) is a recently cloned member of the MMP (matrix metalloproteinase) family. It is highly expressed in the skin by keratinocytes, the developing and regenerating nervous system and a number of other normal human tissues, as well as a number of carcinomas. The MMP28 promoter has previously been cloned and characterized identifying a conserved GT-box that binds Sp1/Sp3 (specificity proteins 1 and 3) proteins and is essential for the basal expression of the gene. The present study demonstrates that MMP28 expression is induced by HDAC (histone deacetylase) inhibitors and that this effect is mediated through the GT-box. Transient transfection assays have shown that the induction of MMP28 expression by the HDAC inhibitior TSA (trichostatin A) is mediated via Sp1 at the GT-box. Immunoprecipitation experiments have shown that the acetylation of Sp1 and Sp3 is increased by TSA treatment; however, no effect on DNA binding was observed. Histone acetyltransferases such as p300 and P/CAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor] increased induction of the MMP28 promoter by Sp1. Knockdown of HDAC1 using siRNA (small interfering RNA) also induces the MMP28 promoter. Oligonucleotide pulldown identified STRAP (serine/threonine kinase receptor-associated protein) as a further protein recruited to the MMP28 promoter and acting functionally with Sp1.
University of East Anglia, Norwich, UK.
Tracey E
TE
Swingler
Lara
L
Kevorkian
Kirsty L
KL
Culley
Sara A
SA
Illman
David A
DA
Young
Andrew E
AE
Parker
Jouko
J
Lohi
Ian M
IM
Clark
D000107:Acetylation / Q000187:drug effects; D001881:Borates / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047468:Immunoprecipitation; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
D001881:Borates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C497121:SP3 protein, human; C403447:STRAP protein, human; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; C012589:trichostatin A; D014635:Valproic Acid; C010634:sodium borate; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted; D056284:Histone Deacetylase 1