Effect of Acetaldehyde on Sp1 Binding and Activation of the Mouse α2(I) Collagen Promoter

Miao, Kai; Potter, James J.; Anania, Frank A.; Rennie-Tankersley, Lynda; Mezey, Esteban

doi:10.1006/abbi.1997.9948

Cited by 21 publications

(8 citation statements)

References 45 publications

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“…In previous studies, we showed that acetaldehyde enhances the activity of the ␣ 2 (I) collagen promoter in stellate cells and that this effect is mediated by increased binding of nuclear proteins, including nuclear factor I to a region, which is located in the TGF-␤-responsive element (12). The binding of Sp1, by contrast, was not affected by acetaldehyde (14). In studies with the mouse ␣ 1 (I) collagen promoter, it was found that the activating effect of acetaldehyde was mediated by increased binding of CCAAT/ enhancer-binding protein ␤ to a region that overlaps with the TGF-␤-responsive element (34,35), but in this case, the activating effect of acetaldehyde was not modified by neutralizing antibody to TGF-␤ (34).…”

Section: The Activating Effect Of Acetaldehyde On Enhancing the Activmentioning

confidence: 87%

“…In previous studies, we showed that acetaldehyde enhances the activity of the murine ␣ 2 (I) collagen promoter in stellate cells and that this effect is mediated by increased binding of nuclear proteins including nuclear factor I to region Ϫ315 to Ϫ295 of the promoter (12). Although Sp1 is important in maintaining basal activity of the ␣ 2 (I) collagen promoter, it plays no role in mediating the effects of acetaldehyde (14).…”

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confidence: 93%

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Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Novitskiy

Potter

Rennie-Tankersley

et al. 2004

Journal of Biological Chemistry

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Hepatic fibrosis is due to the increased synthesis and deposition of type I collagen. Acetaldehyde activates type I collagen promoters. Nuclear factor B (NF-B) was previously shown to inhibit expression of murine ␣ 1 (I) and human ␣ 2 (I) collagen promoters. The present study identifies binding of NF-B, present in nuclear extracts of stellate cells, to a region between ؊553 and ؊537 of the murine ␣ 2 (I) collagen promoter. The NF-B (p65) expression vector inhibited promoter activity. Mutation of the promoter at the NF-B-binding site increased basal promoter activity and abrogated the activating and inhibitory effects of transforming growth factor ␤ and tumor necrosis factor ␣, respectively, on promoter activity. Acetaldehyde increased I B-␣ kinase activity and phosphorylated I B-␣, NF-B nuclear protein, and its binding to the promoter. However, the activating effect of acetaldehyde was not affected by the mutation of the promoter. In conclusion, although acetaldehyde increases the binding of NF-B to the murine ␣ 2 (I) collagen promoter, this binding does not mediate the activating effect of acetaldehyde on promoter activity. The effects of acetaldehyde in increasing the translocation of NF-B to the nucleus with increased DNA binding activity may be important in mediating the effects of acetaldehyde on other genes.

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Section: The Activating Effect Of Acetaldehyde On Enhancing the Activmentioning

confidence: 87%

mentioning

confidence: 93%

Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Novitskiy

Potter

Rennie-Tankersley

et al. 2004

Journal of Biological Chemistry

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“…The activation of ECM genes, in particular that of collagen, is critical in the progression of tissue fibrosis as observed in keloid scars (20,21). Previous literatures have emphasized the role of Sp1 in regulating the expression of genes encoding type 1 collagen (22–24). Zhang et al.…”

Section: Introductionmentioning

confidence: 99%

Targeting of Sp1 transcription factor: a novel therapeutic approach for Keloids, an in vitro analysis

Mukhopadhyay

Khoo

Cheong

et al. 2007

Experimental Dermatology

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Keloid scars are fibroproliferative disorders characterized by the accumulation of extracellular matrix (ECM) components resulting in a fibrotic condition. Several ECM promoters are regulated by Sp1. Thus, our aim was to investigate the role of Sp1 in keloid pathogenesis and investigate the antiproliferative and antifibrotic effects of Wp631 and mitoxantrone, potent inhibitors of Sp1-activated transcription. An elevated level of Sp1 was observed in tissue extracts obtained from keloid tissue. Serum stimulation elevated Sp1 levels in keloid fibroblasts (KF). Under coculture conditions Sp1 seemed to be downregulated. Wp631 and mitoxanthrone in serum growth factors resulted in a reduced expression of ECM components in KF. Both Wp631 and mitoxanthrone were also able to inhibit the proliferation of normal and keloid keratinocytes and fibroblasts significantly. As Wp631 seems to be potent in downregulating the ECM components in KF and also inhibiting the proliferation of these cells it could be explored as a possible therapeutic agent in the treatment of keloids.

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“…Although some publications have described general mechanisms of collagen production by HSCs and have unraveled some signal transduction pathways activated by acetaldehyde, [23][24][25][26][27][28] little is known regarding to the molecular mechanisms whereby acetaldehyde upregulates the expression of the human ␣2(I) collagen gene (COL1A2). Therefore, in this communication we describe molecular events triggered by acetaldehyde that result in COL1A2 transcriptional activation.…”

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confidence: 99%

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

et al. 2005

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Acetaldehyde is fibrogenic and induces the expression of type I collagen genes in hepatic stellate cells. Some of these acetaldehyde-dependent events are mediated by H 2 O 2 and thus establish a direct connection between oxidative stress and collagen upregulation. We localized to the ؊378 to ؊183 region of the ␣2(I) collagen (COL1A2) promoter an acetaldehyde-responsive element (AcRE) functional in human hepatic stellate cells (HHSCs) and investigated molecular mechanisms whereby acetaldehyde stimulates and modulates its transcriptional activity. Because the AcRE co-localized with a previously described transforming growth factor ␤ (TGF-␤)1-responsive element, and both acetaldehyde and this cytokine induce their effects through H 2 O 2 , we investigated whether all fibrogenic actions of acetaldehyde were mediated by this cytokine. Here we show that acetaldehyde-induced COL1A2 upregulation in HHSCs recognizes two distinct but overlapping early and late stages that last from 1 to 6 hours and from 6 to 24 hours, respectively. We present several lines of evidence to show that early acetaldehyde-mediated events are independent of TGF-␤1. These include significant timecourse differences in the expression of COL1A2 and TGF-␤1 mRNAs and inability of neutralizing antibodies to TGF-␤1 to inhibit acetaldehyde-dependent collagen gene transcription and Smad 3 phosphorylation. We also show that although acetaldehyde-dependent upregulation of collagen was PI3K dependent, that of TGF-␤1 was PI3K independent. In conclusion, acetaldehyde-dependent mechanisms involved in COL1A2 upregulation are similar, but not identical, to those of TGF-␤1. We suggest that early acetaldehyde-dependent events induce the late expression of TGF-␤1 and create an H 2 O 2 -dependent autocrine loop that may sustain and amplify the fibrogenic response of this alcohol metabolite. (HEPATOLOGY 2005;42:343-352.)

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Effect of Acetaldehyde on Sp1 Binding and Activation of the Mouse α2(I) Collagen Promoter

Cited by 21 publications

References 45 publications

Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Identification of a Novel NF-κB-binding Site with Regulation of the Murine α2(I) Collagen Promoter

Targeting of Sp1 transcription factor: a novel therapeutic approach for Keloids, an in vitro analysis

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

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