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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 cAMPdependent 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.Tissue inhibitors of metalloproteinases (TIMPs) 1 are natural inhibitors of matrix metalloproteinases (MMPs), a family of proteases that degrade proteins of the extracellular matrix (ECM) (1). These inhibitors play an important role in the control of the homeostasis of the ECM under conditions that are associated with intense connective tissue remodeling such as implantation, embryogenesis, organogenesis, wound repair, arthritis, and cancer invasion (2, 3). Four members of the TIMP family, designated TIMP-1 to TIMP-4, have been identified so far in many species including human (4 -8). These inhibitors differ in many aspects such as tissue-specific expression, solubility, and regulation but share a common antiprotease function because of their ability to form stable enzyme-inhibitor complexes with all members of the MMP family. The balance between MMPs and TIMPs is a key element that controls the turnover of the ECM and is itself under the influence of a large variety of growth factors and cytokines that transcriptionally regulate MMP and TIMP expression. Whereas some of these factors such as transforming growth factor ␤ have a coordinated effect that decreases ECM degradation by up-regulating TIMP and down-regulating MMP expression (9, 10), other factors such as interleukin-1, interleukin-6, or oncostatin M have a much less predictable effect on the ECM because they simultaneously up-or down-regulate MMP and TIMP expression (11)(12)(13)(14).The molecular basis for the transcriptional regulation of MMP and TIMP expression has been investigated, and several cis-acting elements in the promoter of many MMPs and TIMPs responsible for transcription control have been identified. In particular, a PEA-3 motif and an AP-1 motif located in close proximity in the promoter of many MMPs and TIMPs have been shown to mediate their enhanced expression by phorbol esters and serum factors (15), and a transform...

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