Inhibition of Transforming Growth Factor (TGF)-β1–Induced Extracellular Matrix with a Novel Inhibitor of the TGF-β Type I Receptor Kinase Activity: SB-431542

Laping, Nicholas J.; Grygielko, Eugene T.; Mathur, Ashwini; Butter, Sebastian; Bomberger, Jennifer M.; Tweed, Christopher W.; Martin, W; Fornwald, James A.; Lehr, Ruth; Harling, John D.; Gaster, Laramie M.; Callahan, James F.; Olson, Beth

doi:10.1124/mol.62.1.58

Cited by 587 publications

(442 citation statements)

References 39 publications

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“…For one, other TGF-␤1 signaling intermediates such as mitogen-activated protein kinases have been found to induce collagen and fibronectin gene expression. 34,35 Moreover, a wide array of profibrotic cytokines in addition to TGF-␤1, such as platelet-derived growth factor, has been linked to the pathogenesis of OB. 36 In summary, our observations establish that Smad3 is an essential, novel component of the fibroproliferative response in experimental OB wherein TGF-␤1 and CTGF are abundantly expressed.…”

Section: Discussionmentioning

confidence: 99%

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Ramirez

Takagawa

Sekosan

et al. 2004

The American Journal of Pathology

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Chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-␤1 (TGF-␤1) has been implicated in the tissue remodeling response associated with OB. Therefore, its intracellular signal transducer, Smad3, is a prime target of investigation. Herein, we examine the role of TGF-␤1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-␤1 was detectable within infiltrating mononuclear cells early after transplantation. Throughout the last 20 years, lung transplantation has evolved into an accepted treatment option for patients with end-stage lung disease because of emphysema, pulmonary fibrosis, pulmonary hypertension, and cystic fibrosis. 1 However, chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the major obstacle to long-term survival after lung transplantation. 2 Clinically, OB is characterized by airflow limitation, defined by a 20% decline in forced expiratory volume in 1 second (FEV 1 ), and is often complicated by recurrent lower respiratory tract infections. The histological hallmark of OB is the presence of obstructing intraluminal polyps comprised of fibromyxoid granulation tissue and plaques of dense submucosal eosinophilic scar on lung biopsy. OB can complicate up to 60% of lung allografts and becomes increasingly prevalent the further removed from the transplant operation. 3 Progressive OB ultimately results in worsening hypoxemia and death.Many studies on the pathogenesis of OB have concentrated on the role of cellular allogenic immune responses during OB development. However, fibroproliferation and tissue remodeling clearly play an important role in its pathogenesis because OB is characterized by the accumulation of fibroblasts and the excessive deposition of connective tissue matrix within the lumen of the affected bronchioles. The factors that initiate and maintain fibroproliferation and tissue remodeling within the airway lumen in OB have not been fully elucidated. One candidate factor is transforming growth factor (TGF)-␤, a pleiotropic cytokine with potent profibrotic activities. 4 Extensively studied in solid organ transplantation, TGF-␤ has been found to have beneficial effects on alloimmunity. For instance, overexpression of a TGF-␤ transgene leads to marked reductions in acute rejection and prolongation of graft survival in experimental heart and

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Section: Discussionmentioning

confidence: 99%

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Ramirez

Takagawa

Sekosan

et al. 2004

The American Journal of Pathology

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“…The kinetics of Smad relocalization to the cytoplasm mirrors receptor inactivation and hence the slow fading of the signal. This has been demonstrated directly because if signaling is terminated prematurely by adding a specific type I receptor inhibitor SB-431542 [25,26], nuclear accumulation of Smads begins to decrease immediately, causing the bulk of Smads to relocalize to the cytoplasm within 2 h [24]. How do the nuclear Smads "know", however, that the receptors have been inactivated?…”

Section: Evidence For Smad Nucleocytoplasmic Shuttlingmentioning

confidence: 99%

Nucleocytoplasmic shuttling of Smad proteins

2008

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Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor β (TGF-β)-superfamily signals from transmembrane receptors into the nucleus. It is now clear that the nucleocytoplasmic distributions of Smads, in both the absence and the presence of a TGF-β-superfamily signal, are not static, but instead the Smads are continuously shuttling between the nucleus and the cytoplasm in both conditions. This article presents the evidence for continuous nucleocytoplasmic shuttling of Smads. It then reviews different mechanisms that have been proposed to mediate Smad nuclear import and export, and discusses how the Smad steady-state distributions in the absence and the presence of a TGF-β-superfamily signal are established. Finally, the biological relevance of continuous nucleocytoplasmic shuttling for signaling by TGF-β superfamily members is discussed.

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“…Hnf6 Ϫ/Ϫ BMEL cells were incubated with SB431542, a compound known to inhibit phosphorylation of Smads by T␤RI, 43,44 or with PD98059, an inhibitor of the Erk pathway. Both compounds reduced Foxa1 mRNA levels (Fig.…”

Section: Foxa1mentioning

confidence: 99%

Transcription Factor Hnf–6/Oc–1 Inhibits the Stimulation of the Hnf–3 /Foxa1 Gene by Tgf–B in Mouse Liver

et al. 2004

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A network of liver-enriched transcription factors controls differentiation and morphogenesis of the liver. These factors interact via direct, feedback, and autoregulatory loops. Previous work has suggested that hepatocyte nuclear factor (HNF)-6/OC-1 and HNF-3␣/FoxA1 participate coordinately in this hepatic network. We investigated how HNF-6 controls the expression of Foxa1. We observed that Foxa1 expression was upregulated in the liver of Hnf6 ؊/؊ mouse embryos and in bipotential mouse embryonic liver (BMEL) cell lines derived from embryonic Hnf6 ؊/؊ liver, suggesting that HNF-6 inhibits the expression of Foxa1. Because no evidence for a direct repression of Foxa1 by HNF-6 was found, we postulated the existence of an indirect mechanism. We found that the expression of a mediator and targets of the transforming growth factor beta (TGF-␤) signaling was increased both in Hnf6 ؊/؊ liver and in Hnf6 ؊/؊ BMEL cell lines. Using these cell lines, we demonstrated that TGF-␤ signaling was increased in the absence of HNF-6, and that this resulted from upregulation of TGF-␤ receptor II expression. We also found that TGF-␤ can stimulate the expression of A network of liver-enriched transcription factors (LETFs) controls differentiation and morphogenesis of the liver. 1-3 It comprises factors from several families that have been identified through biochemical and genetic studies. These include the CCAAT/enhancer binding proteins, the proline acidrich factors, the homeodomain proteins of the hepatocyte nuclear factor (HNF)-1 family, winged helix proteins (HNF-3/FoxA), nuclear receptors (HNF-4, LXR, FXR and FTF/hB1F/CPF families), and the Onecut (OC) factors (HNF-6/OC-1, OC-2 and OC-3). These LETFs regulate the expression of genes whose products control the development of the liver and its physiological functions. Evidence for a network of LETFs stemmed from studies based on transfection of hepatoma lines, which showed that HNF-1␣ and HNF-4 can control each other. 4 -7 Other groups extended this notion by showing that a combination of LETFs acting in synergy can directly regulate the expression of a transcription factor

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Inhibition of Transforming Growth Factor (TGF)-β1–Induced Extracellular Matrix with a Novel Inhibitor of the TGF-β Type I Receptor Kinase Activity: SB-431542

Cited by 587 publications

References 39 publications

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model

Nucleocytoplasmic shuttling of Smad proteins

Transcription Factor Hnf–6/Oc–1 Inhibits the Stimulation of the Hnf–3 /Foxa1 Gene by Tgf–B in Mouse Liver

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