Halofuginone inhibition of <i>COL1A2</i> promoter activity via a c‐Jun–dependent mechanism

McGaha, Tracy L.; Kodera, Takao; Spiera, Harry; Stan, Alexandru C.; Pines, Mark; Bona, Constantin A.

doi:10.1002/art.10549

Cited by 32 publications

(21 citation statements)

References 59 publications

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“…Among the potential factors, we chose to study Elk-1 and c-JUN because they have been shown to be involved in the COL1 and OPN expression regulated by TGF-b, TNF-a, and other activated steroid hormone receptors [Sodek et al, 1995;McGaha et al, 2002;Verrecchia et al, 2002]. In our current study, oscillatory flow significantly induced the phosphorylation levels of both Elk-1 and c-JUN (Fig.…”

Section: Temporal Differences In Mapk Activationsmentioning

confidence: 77%

Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow

Haga

et al. 2006

J of Cellular Biochemistry

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We investigated the effects of oscillatory flow in regulating the gene expressions of type I collagen (COL1, the main component of human bone tissues) and osteopontin (OPN, the key gene for calcium deposition) in human osteoblast-like (MG-63) cells, and the roles of mitogen-activated protein kinases (MAPKs) in this regulation. The cells were subjected to oscillatory flow (0.5 +/- 4 dyn/cm(2)) or kept under static condition for various time periods (15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 16 h). Oscillatory flow caused significant up-regulations of both COL1 and OPN gene expressions over the 16 h of study, and a transient activation of MAPKs was starting at 15 min and declining to basal level in 2 h. The flow-induction of COL1 was blocked by an ERK inhibitor (PD98059) and reduced by a JNK inhibitor (SP600125), whereas that of OPN was abolished by PD98059. Analysis of the cis-elements in the COL1 and OPN promoters suggests the involvement of transacting factors Elk-1 and AP-1 in the transcription regulation. The ERK inhibitor (PD98059) blocked Elk-1 phosphorylation, as well as COL1 and OPN gene expression. The JNK inhibitor (SP600125) abolished c-jun phosphorylation and COL1 expression. These results suggest that the flow-induction of OPN was mediated through the ERK-Elk1-OPN pathway, and that COL1 was regulated by both the ERK-Elk1-COL1 and JNK-c-JUN-COL1 pathway.

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Section: Temporal Differences In Mapk Activationsmentioning

confidence: 77%

Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow

Haga

et al. 2006

J of Cellular Biochemistry

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“…Thus, in addition to regulating target genes via binding to the Egr-response element, Egr-1 may also influence genes that are controlled by AP-1 sites via their interaction with c-Jun. Halofuginone enhances basal and mitogen-mediated phosphorylation of c-Jun, and this is correlated with enhanced DNA binding and transcriptional activation of an AP-1 complex (McGaha et al 2002a) suggesting that halofuginone-dependent Egr-1 gene expression is mediated by c-Jun. C-Jun is also a negative regulator of collagen type I synthesis through the AP-1 regulatory elements in its promoter (Fisher et al 2000).…”

Section: Discussionmentioning

confidence: 95%

Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL–1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone

et al. 2006

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Tyrosine phosphatase PRL-1 is one of the immediate-early genes up-regulated during liver regeneration and is apparently involved in cell proliferation. Previously, we have demonstrated that halofuginone, an inhibitor of collagen type I synthesis, prevents liver fibrosis and improves cirrhotic liver regeneration. In this study, we evaluated the effect of halofuginone on PRL-1 expression, its cellular localization in vitro and during liver regeneration, and fibrosis progression in vivo. In culture, halofuginone increased PRL-1 expression in primary rat hepatocytes and in hepatocellular carcinoma (HCC) cell lines, the former being more sensitive to halofuginone. The halofuginone-dependent increase in PRL-1 gene expression was correlated with an increase in the transcription factor early growth response-1 (Egr-1) and inversely correlated with the inhibition of cell proliferation. Halofuginone arrested HepG2 and Huh7 cell lines at the G1 phase, whereas Hep3B cells were arrested at G2/M, probably because of a reduction in the synthesis of cyclins D1 and B1 in all HCC cells and increased cyclin A in Hep3B cells. Halofuginone also affected the PRL-1 sub-cellular localization that was cell-cycle-dependent. In addition, halofuginone augmented PRL-1 expression in the remnant liver after partial hepatectomy and in chemically induced fibrosis in rats; this was accompanied by increased expression of insulin-like growth factor binding protein 1 (IGFBP-1), another immediate-early gene of regeneration. The regulation of the expression of the early genes of regeneration such as PRL-1 and IGFBP-1 is thus part of the mode of action of halofuginone and results in the prevention of liver fibrosis and improved cirrhotic liver regeneration.

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“…During the last decade HAL was investigated as an antifibrotic agent in various in vivo fibrosis models (reviewed in Ref. 11) and suggested to be a specific inhibitor of procollagen type I expression for various collagen-expressing cells (12)(13)(14)(15). More recently, HAL was shown to partly reverse established thioacetamide-induced rat liver fibrosis (16).…”

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confidence: 99%

Halofuginone Induces Matrix Metalloproteinases in Rat Hepatic Stellate Cells via Activation of p38 and NFκB

Popov

Patsenker

Bauer

et al. 2006

Journal of Biological Chemistry

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The semisynthetic plant alkaloid halofuginone (HAL) was reported to prevent and partly reverse experimental liver fibrosis. However, its mechanisms of action are poorly understood. We therefore aimed to determine the antifibrotic potential of HAL and to characterize involved signal transduction pathways in hepatic stellate cells (HSCs). Results were compared with its in vivo effects in a rat model of reversal of established liver fibrosis induced by thioacetamide. In vitro HAL inhibited HSC proliferation and migration dose dependently at submicromolar concentrations. HAL (200 nM) up-regulated matrix metalloproteinase (MMP)-3 and MMP-13 expression between 10-and 50-fold, resulting in a 2-to 3-fold increase of interstitial collagenase activity. Procollagen ␣1(I) and MMP-2 transcript levels were suppressed 2-to 3-fold, whereas expression of other profibrogenic mRNAs remained unaffected. p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor B (NFB) pathways were activated by HAL, and specific inhibitors of p38 MAPK and NFB dose dependently inhibited MMP-13 induction. Treatment with HAL did not affect HSC viability, and observed effects were reversible after its removal. In vivo HAL upregulated MMP-3 and -13 mRNA expression 1.5-and 2-fold, respectively, in cirrhotic rats, whereas tissue inhibitor of metalloproteinase-1 was suppressed by 50%. In conclusion, submicromolar concentrations of HAL inhibit HSC proliferation and migration and up-regulate their expression of fibrolytic MMP-3 and -13 via activation of p38 MAPK and NFB. The remarkable induction of MMP-3 and -13 makes HAL a promising agent for antifibrotic combination therapies.

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Halofuginone inhibition of COL1A2 promoter activity via a c‐Jun–dependent mechanism

Cited by 32 publications

References 59 publications

Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow

Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow

Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL–1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone

Halofuginone Induces Matrix Metalloproteinases in Rat Hepatic Stellate Cells via Activation of p38 and NFκB

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