NF-Y and Sp1 cooperate for the transcriptional activation and cAMP response of human tissue inhibitor of metalloproteinases-2.
The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) is a key determinant in the homeostasis of the extracellular matrix. We have identified two cis-acting elements involved in the transcriptional regulation of TIMP-2. The first is an inverted CCAAT box located at position -73 to -69 in the TIMP-2 promoter that binds the transcription factor NF-Y. The second is a GAGGAGGGGG motif located at position -107 to -98, that binds the transcription factors Sp1 and Sp3. NF-Y and Sp1 cooperate for the basal transcription activity of the promoter. We then determined that TIMP-2 is transcriptionally up-regulated by cAMP analogs. Up-regulation of TIMP-2 by dibutyryl cAMP is a delayed response that requires de novo protein synthesis and does not affect RNA stability. The NF-Y and the Sp1 binding site are both involved in cAMP-dependent up-regulation of TIMP-2. Whereas NF-Y is essential for cAMP mediated regulation, Sp1 alone is not sufficient but enhances the activity of NF-Y. Dibutyryl cAMP has no effect on the expression of MMP-2 and MMP-9 and switches the MMP-TIMP balance in favor of the inhibitor.
Zhong
Z D
ZD
Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
Hammani
K
K
Bae
W S
WS
DeClerck
Y A
YA
D016475:3T3 Cells; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D000242:Cyclic AMP / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016329:Sp1 Transcription Factor; D019716:Tissue Inhibitor of Metalloproteinase-2; D000242:Cyclic AMP