Persistent Down-Regulation of Fli1, a Suppressor of Collagen Transcription, in Fibrotic Scleroderma Skin

Kubo, Masahide; Czuwara-Ladykowska, Joanna; Moussa, Omar; Markiewicz, Margaret; Smith, Edwin A.; Silver, Richard M.; Jabłońska, Stefania; Błaszczyk, M; Watson, Dennis K.; Trojanowska, Maria

doi:10.1016/s0002-9440(10)63685-1

Cited by 158 publications

(159 citation statements)

References 45 publications

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“…For immunostainings, we used primary antibodies against total Smad1 (Abcam, Cambridge, MA) and phospho-Smad1 (17). Incubations with the primary antibodies diluted in horse serum in PBS to the indicated concentrations were performed overnight in a humidified chamber at 4°C as previously described (18). After 3 rinses in PBS, binding sites of the primary antibodies were detected with biotinylated IgG, and the sites of peroxidase activity were visualized by using diaminobenzidine.…”

Section: Methodsmentioning

confidence: 99%

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

Pannu¹,

Asano²,

Nakerakanti³

et al. 2008

Arthritis & Rheumatism

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Objective. Activation of Smad1 signaling has recently been implicated in the development of fibrosis. The goal of the present study was to gain further insights into activation of the Smad1 pathway in fibrosis in systemic sclerosis (SSc) and to determine whether this pathway is targeted by the antifibrotic drug imatinib mesylate.Methods. Levels of phosphorylated Smad1 and total Smad1 were examined in SSc and control skin biopsy samples by immunohistochemistry and in cultured fibroblasts by Western blotting. Activity of the CCN2 promoter was examined by a luciferase reporter gene assay. Interactions of Smad1 with the CCN2 promoter were examined by in vitro and in vivo DNA binding assays. Expression of the nonreceptor tyrosine kinase c-Abl and Smad1 was blocked using respective small interfering RNA.Results. Total and phosphorylated Smad1 levels were significantly elevated in SSc skin biopsy samples and in cultured SSc fibroblasts and correlated with elevated CCN2 protein and CCN2 promoter activity. DNA binding assays demonstrated that Smad1 was a direct activator of the CCN2 gene. Small interfering RNA-mediated depletion of Smad1 in SSc fibroblasts normalized the production of CCN2 and collagen. Imatinib mesylate blocked activation of the Smad1 pathway in transforming growth factor ␤-stimulated control fibroblasts and reversed activation of this pathway in SSc fibroblasts. Likewise, blockade of c-Abl abrogated activation of the Smad1 pathway in SSc fibroblasts.Conclusion. Our findings demonstrate that activation of Smad1 signaling occurs in a subset of SSc patients and contributes to persistent activation of SSc fibroblasts. Demonstration that the Smad1/CCN2 pathway is blocked by imatinib mesylate further clarifies the mechanism of the antifibrotic effects of this compound.

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Section: Methodsmentioning

confidence: 99%

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

Pannu¹,

Asano²,

Nakerakanti³

et al. 2008

Arthritis & Rheumatism

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“…Reduction of Fli1 gene expression by TGF-␤ suggested that the presence of Fli1 might interfere with TGF-␤/Smad signaling. To test this possibility, we used previously generated adenoviral vector carrying Fli1 (AdFli1) (29). Cells were transduced with 10 MOI of AdFli1, which resulted in 8 -10-fold induction of the Fli1 mRNA level above the endogenous levels.…”

Section: Opposite Effects Of Ets1 and Fli1 On The Expression Levels Omentioning

confidence: 99%

“…Fli1 and Ets1 have been previously associated with regulation of ECM genes, including collagen type I and tenascin-C (14,15). Importantly, reduction of Fli1 expression correlated with elevated collagen synthesis in patients with scleroderma, a systemic fibrotic disease, suggesting that absence of Fli1 may directly contribute to the process of fibrosis (29). On the other hand, elevated expression of Ets1 is often present in stromal fibroblasts and endothelial cells in various tumors (5).…”

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confidence: 99%

Fli1 and Ets1 Have Distinct Roles in Connective Tissue Growth Factor/CCN2 Gene Regulation and Induction of the Profibrotic Gene Program

Nakerakanti

Kapanadze

Yamasaki

et al. 2006

Journal of Biological Chemistry

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110

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“…1). Furthermore, different Ets factors may have reciprocal functions: Ets1 and Fli1 differentially regulate the collagen α2(I) promoter [Czuwara-Ladykowska et al, 2001;Kubo et al, 2003]. Thus, the precise balance or "regulated imbalance" between cancer/metastasispromoting and-inhibiting Ets factor activities, which differentially regulate specific target genes, contributes to tissue homeostasis or tumor progression, respectively.…”

Section: Ets Target Genesmentioning

confidence: 99%

Ets proteins in biological control and cancer

Hsu

Trojanowska

Watson

2004

J of Cellular Biochemistry

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The Ets family consists of a large number of evolutionarily conserved transcription factors, many of which have been implicated in tumor progression. Extensive studies on this family of proteins have focused so far mainly on the biochemical properties and cellular functions of individual factors. Since most of the Ets factors can bind to the core consensus DNA sequence GGAA/T in vitro, it has been a challenge to differentiate redundant from specific functions of various Ets proteins in vivo. Recent findings, however, suggest that such apparent redundancy may in fact be a central component of a network of differentially regulated specific Ets factors, resulting in distinct biological and pathological consequences. The programmed "Ets conversion" appears to play a critical role during tumor progression, especially in control of cellular changes during epithelial-mesenchymal transition and metastasis. Coordination of multiple Ets gene functions also mediates interactions between tumor and stromal cells. As such, these new insights may provide a novel view of the Ets gene family as well as a focal point for studying the complex biological control involved in tumor progression. KeywordsEts; transcriptional regulation; ECM; cancer; invasion; metastasis; EMT; epithelium; stroma The Ets family of proteins consists of a large number of evolutionarily conserved transcription factors. There are 25 human and 26 murine Ets family members. Ets factors control specific genes that perform critical roles in diverse processes, including cell proliferation, apoptosis, differentiation, lymphoid cell development, angiogenesis, and invasiveness [Sementchenko and Watson, 2000]. To date, studies in the field have largely focused on individual Ets factors and have indeed yielded valuable, albeit fragmented, information. Recent findings, on the other hand, have suggested that several Ets factors may participate in a coordinated program that modulates cell migration and invasiveness, thus affecting tumor progression toward metastasis. In this review, we will examine the recent progress in Ets biology and provide a forum for discussion on a systemic view of Ets functions. Detailed descriptions of Ets proteins and their functions have been provided in several recent reviews [Watson and Seth, 2000;Watson et al., 2001;Dittmer, 2003;Oikawa and Yamada, 2003].Cancer results from a multi-step series of genetic changes that lead to essential alterations in cell physiology such as loss of growth controls and normal apoptotic response as well as sustained angiogenesis, invasion, and metastasis [Hanahan and Weinberg, 2000]. While it is known that most human tumors are derived from epithelial cells that have undergone multiple genetic alterations [Hanahan and Weinberg, 2000], it is also becoming clear that the alterations

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Persistent Down-Regulation of Fli1, a Suppressor of Collagen Transcription, in Fibrotic Scleroderma Skin

Cited by 158 publications

References 45 publications

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

Fli1 and Ets1 Have Distinct Roles in Connective Tissue Growth Factor/CCN2 Gene Regulation and Induction of the Profibrotic Gene Program

Ets proteins in biological control and cancer

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