Regulation of Plasminogen Activator Inhibitor-1 Expression by Transforming Growth Factor-β-induced Physical and Functional Interactions between Smads and Sp1

Datta, Pran K.; Blake, M C; Moses, Harold L.

doi:10.1074/jbc.c000508200

Cited by 129 publications

(115 citation statements)

References 25 publications

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“…The role of Smad3 in induction of TIMP-1 gene expression by TGF-␤1 has also been demonstrated in human dermal fibroblasts and confirmed in Smad3 KO mouse embryo fibroblasts (16). Likewise, we found that induction of the antiproteinase PAI-1 by TGF-␤1 is very dependent on Smad3, as suggested from previous work (14,56,57).…”

Section: An Imbalance In Matrix Protein Metabolism Favoring Degradatisupporting

confidence: 74%

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Bonniaud

Kolb

Galt

et al. 2004

The Journal of Immunology

350

258

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Transforming growth factor-β1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-β1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-β1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).

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Section: An Imbalance In Matrix Protein Metabolism Favoring Degradatisupporting

confidence: 74%

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Bonniaud

Kolb

Galt

et al. 2004

The Journal of Immunology

350

258

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“…Since Sp1 interacts with many other proteins [29], it is reasonable to speculate that its specificity may be brought about by the recruitment of other nuclear factors onto the T-BET promoter. For example, it is well-documented that both in vivo and in vitro, SMAD proteins associate with Sp1 [33][34][35][36]. Specifically, Sp1 physically interacts with SMAD2 and SMAD4 , and indirectly with SMAD3 through SMAD3 0 s association with SMAD2 and/or SMAD4 [33].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

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Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-c gene expressionin NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-c secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-c protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-c are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-c expression.

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“…41 Sp1 consensus sites are also present in several promoters of the downstream targets of TGF-b1, and are required to support TGF-b1-mediated transcription activation. 42,43 In addition, Sp1 directly contributes to the expression of a wide variety of matrix genes. 32 Our present results provide additional evidence to support for the crucial role of Sp1 in nephritic fibrosis.…”

Section: Suppression Of Rat Kidney Fibrosis By Sp1 Decoymentioning

confidence: 99%

Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction

et al. 2005

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Tubulointerstitial fibrosis is the consequence of an injury characterized by the accumulation of excess collagen and other extracellular matrix components, resulting in the destruction of the normal kidney architecture and subsequent loss of function. A transcription factor Sp1, originally described as a ubiquitous transcription factor, is involved in the basal expression of extracelluar matrix genes and may, therefore, be important in fibrotic processes. Here, we report on the design of a ring-Sp1 decoy oligonucleotide, containing the consensus Sp1 binding sequence in a single decoy molecule without an open end, to create a novel therapeutic strategy for fibrosis. The ring-Sp1 decoy oligonucleotide is highly resistant to degradation by nucleases or serum compared to the conventional phosphorothioated doublestranded Sp1 decoy oligonucleotide, and effectively suppressed the expression of transforming growth factor-b1 and fibronectin, the binding of Sp1 to the promoter region of these genes, and proliferation in response to serum in normal rat kidney fibroblasts. Moreover, treatment with the ring-Sp1 decoy in vivo significantly attenuates extracellular matrix gene expression in the rat kidney in which a unilateral ureteral obstruction had been induced. These results suggest that the ring-Sp1 decoy oligonucleotide represents promising therapeutic alternative to the conventional treatment of fibrotic disorders.

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Regulation of Plasminogen Activator Inhibitor-1 Expression by Transforming Growth Factor-β-induced Physical and Functional Interactions between Smads and Sp1

Cited by 129 publications

References 25 publications

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Transcriptional control of human T‐BET expression: The role of Sp1

Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction

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