Matrix metalloproteinase-1 (MMP-1) is one of three collagenases that can degrade the interstitial collagens, types I, II, and III at neutral pH. As these collagens are the most abundant proteins in the body, collagenase plays a critical role in modeling and remodeling the extracellular matrix. Therefore, it is not surprising that MMP-1 gene expression can be regulated at multiple points. Procollagenase can be activated by mechanisms that generate an active enzyme with differing specific activities, and the active enzyme can be inhibited by complexing with either the tissue inhibitor of metalloproteinases (TIMPs) or alpha 2 macroglobulin. The activator protein-1 (AP-1) site in the collagenase promoter plays a prominent role in the transcriptional control of the collagenase gene. It is essential for basal transcription, and contributes to induction by phorbol esters, although other sites in the proximal promoter are essential. In contrast, transactivation by cytokines such as Interleukin-1 depends on sequences in more distal regions of the promoter. Posttranscriptional mechanisms also regulate gene expression, and several cytokines and growth factors increase the stability of the collagenase transcript. Finally, glucocorticoid hormones repress transcription of the collagenase gene by the interaction of glucocorticoid receptors with the AP-1 proteins, Fos and Jun. Retinoids also suppress transcription by mechanisms that involve down-regulation of fos and jun mRNA, sequestration of Fos and Jun proteins, and the formation of complexes of retinoic acid receptors (RAR/RXR heterodimers) and AP-1 proteins on the DNA. These multiple points of regulation assure precise control of collagenolytic activity in a variety of physiologic and pathologic conditions.

SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor copressor) mediate transcriptional repression of important regulators that are involved in many signaling pathways. SMRT and N-CoR are related proteins that form complexes with mSin3A͞B and histone deacetylases to induce local chromatin condensation and transcriptional repression. However, SMRT is substantially smaller than N-CoR, lacking an N-terminal domain of approximately 1,000 aa that are present in N-CoR. Here, we report the identification of SMRTextended (SMRTe), which contains an N-terminal sequence that shows striking similarity with N-CoR. As in N-CoR, this SMRTe-N-terminal domain also represses basal transcription. We find that SMRTe expression is regulated during cell cycle progression and SMRTe transcripts are present in many embryonic tissues. These data redefine a structurally and functionally more related nuclear receptor corepressor family and suggest an additional role for SMRTe in the regulation of cycle-specific gene expression in diverse signaling pathways.Transcriptional repression plays an important role in the proper regulation of cell growth, differentiation, and development (1-3). In one mechanism of transcriptional inhibition, a repressor competes with an activator for DNA binding. Alternatively, transcriptional repressors also can inhibit basal transcription through direct interaction with general transcription factors, or indirectly by promoting chromatin condensation, thereby preventing the loading of general transcription factors to the promoter (1-3).Transcriptional repression by unliganded nuclear receptors such as TR (thyroid hormone receptor) and RAR (retinoic acid receptor) provide an excellent system for dissecting the pathways that lead to gene repression. TR and RAR play important roles in the regulation of cell growth, differentiation, and homeostasis. In the absence of hormone, TR and RAR actively repress target gene expression (4). Unliganded TR and RAR interact with the corepressors SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor corepressor) (5, 6), which are components of corepressor complexes that also contain mSin3A͞B and histone deacetylases (7-9). The binding of hormone to these receptors induces active conformations (10-12), causing dissociation of the corepressor complex. A coactivator complex then is recruited, leading to transcriptional activation (13).In addition to TR and RAR, SMRT and N-CoR interact with other transcriptional regulators involved in various signaling pathways. These regulators include the orphan nuclear receptors COUP-TF1 (14), Rev-Erb, RVR (15), and DAX-1 (16), the latter of which is involved in congenital X-linked adrenal hypoplasia (17). SMRT and N-CoR also interact with antagonist-bound progesterone and estrogen receptors (18,19), suggesting that the corepressors may play a role in determining the antagonistic activities of antihormones. Functional complexes containing SMRT and N-CoR al...

SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors that contain separable domains capable of interacting with unliganded nuclear receptors and repressing basal transcription. To decipher the mechanisms of receptor interaction and transcriptional repression by SMRT/N-CoR, we have characterized protein-protein interacting surfaces between SMRT and nuclear receptors and defined transcriptional repression domains of both SMRT and N-CoR. Deletional analysis reveals two individual nuclear receptor domains necessary for stable association with SMRT and a C-terminal helix essential for corepressor dissociation. Coordinately, two SMRT domains are found to interact independently with the receptors. Functional analysis reveals that SMRT contains two distinct repression domains, and the corresponding regions in N-CoR also repress basal transcription. Both repression domains in SMRT and N-CoR interact weakly with mSin3A, which in turn associates with a histone deacetylase HDAC1 in a mammalian two-hybrid assay. Far-Western analysis demonstrates a direct protein-protein interaction between two N-CoR repression domains with mSin3A. Finally we demonstrate that overexpression of full-length SMRT further represses basal transcription from natural promoters. Together, these results support a role of SMRT/N-CoR in corepression through the utilization of multiple mechanisms for receptor interactions and transcriptional repression.

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