Activation of Proα2(I) Collagen Promoter during Hepatic Fibrogenesis in Transgenic Mice

Inagaki, Yutaka; Truter, Sharada L.; Bou‐Gharios, George; Garrett, L A; Crombrugghe, B. de; Nemoto, Tomoyuki; Greenwel, Patricia

doi:10.1006/bbrc.1998.9345

Cited by 35 publications

(28 citation statements)

References 21 publications

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“…The promoter of ␣2 (I) collagen, another important ECM component, has been shown to be a direct target of TGF-␤ signaling. 59 In HSCs, collagen expression was induced 16 hours after the addition of TGF-␤1. In MFBs no increase of collagen message was detected as a consequence of TGF-␤1 supply.…”

Section: Discussionmentioning

confidence: 99%

Modulation of transforming growth factorβ response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts

et al. 2000

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Section: Discussionmentioning

confidence: 99%

Modulation of transforming growth factorβ response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts

et al. 2000

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“…In some experiments, mice were fed a 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet (Oriental Yeast, Tokyo, Japan) or a methionine choline‐deficient ethionine‐supplemented diet (MP Biomedicals, Santa Ana, CA). Bile duct ligation and 70% partial hepatectomy were performed as described 17, 18…”

Section: Methodsmentioning

confidence: 99%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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“…The COL1A2-luciferase (Lux) reporter construct contains sequences of the promoter region of α2(I) collagen gene (COL1A2) essential for basal and TGF-β-stimulated transcription fused to the luciferase reporter gene [20]. Sp1-binding site and Smad-binding element exist in the sequences of the promoter region of COL1A2 [20].…”

Section: Methodsmentioning

confidence: 99%

“…Sp1-binding site and Smad-binding element exist in the sequences of the promoter region of COL1A2 [20]. Rested mesangial cells (1 × 10 6 /well) were transiently transfected with COL1A2-Lux using the lipofectin method (FuGene 6 ; Boehringer Mannheim) according to the manufacturer’s recommendations.…”

Section: Methodsmentioning

confidence: 99%

Involvement of p300 in TGF-β/Smad-Pathway-Mediated α2(I) Collagen Expression in Mouse Mesangial Cells

Kanamaru

Nakao²,

Tanaka³

et al. 2004

Nephron Exp Nephrol

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Background: Transforming growth factor beta 1 (TGF-β1) induces α2(I) collagen gene (COL1A2) expression in mesangial cells through physical and functional cooperation of Smad proteins and Sp1. A transcriptional coactivator, p300, is also suggested to play an important role in TGF-β1/Smad signal transduction. However, the role of p300 in TGF-β1/Smad-pathway-mediated transcriptional activation of the COL1A2 gene in mesangial cells is still obscure. Methods: Endogenous p300 expression and its modulation by TGF-β1 were evaluated by Western blotting and immunofluorescence. The physical interaction of p300 with Smad2/3 was examined by immunoprecipitation followed by Western blotting. The functional role of p300 in TGF-β1/Smad-pathway-mediated COL1A2 transcription was investigated in cotransfection experiments using a COL1A2 promoter-luciferase reporter gene construct and p300 expression plasmids. Results: TGF-β1 induced COL1A2 gene expression in cultured mouse mesangial cells which was blocked by overexpression of inhibitory Smad7. In addition, TGF-β1-induced nuclear export of endogenous Smad7 was observed in mouse mesangial cells. Endogenous p300 was expressed in the nucleus of the cells. TGF-β1 induced interaction of endogenous p300 with Smad2/3, and a dominant negative construct of p300 inhibited the TGF-β1-induced COL1A2 expression in cultured mouse mesangial cells. Conclusions: p300 may be involved in TGF-β1/Smad-pathway-mediated type I collagen gene transcription in mouse mesangial cells. Our findings would reveal a molecular basis of TGF-β1-induced type I collagen gene transcription in mouse mesangial cells.

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Activation of Proα2(I) Collagen Promoter during Hepatic Fibrogenesis in Transgenic Mice

Cited by 35 publications

References 21 publications

Modulation of transforming growth factorβ response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts

Modulation of transforming growth factorβ response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Involvement of p300 in TGF-β/Smad-Pathway-Mediated α2(I) Collagen Expression in Mouse Mesangial Cells

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