Organization of Human ACAT-2 Gene and Its Cell-Type-Specific Promoter Activity

Song, Bei; Qi, Wei; Xia, Yang; Chang, Catherine C.Y.; Zhu, Jun; Chang, Ta−Yuan; Li, Bo-Liang

doi:10.1006/bbrc.2001.4612

Cited by 25 publications

(39 citation statements)

References 47 publications

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“…Dailly (Dailly et al, 2001) analyzed the promoter activity of the IGFBP-6 gene 5' -flanking region in the SaOS-2 and U-2OS cell lines. Deletion analysis showed the promoted activity of IGFBP-6 gene requires the -1,731 to +154 bp sequence of the gene promoter, and the important elements include a putative RARE, an AP-2 site, a CACCC box, and an Sp1 site (Dailly et al, 2001;Song et al, 2001). We found that estrogen activity in SaOS-2 cells is primarily associated with the -44 to +118 region of the IGFBP-6 gene promoter that contains the liganded-ER binding site in the -9 to +1 region (Figure 2 and 4).…”

Section: Discussionmentioning

confidence: 99%

“…Structural and functional analyses of the IGFBP-6 gene promoter have been performed (Hodzic et al, 1997;Dailly et al, 2001), and the 5'-promoter region contains retinoic acid response elements, CAAT boxes, CACCC boxes, NF-1, and activated protein-1 (AP-1)/AP-2 sites (Dailly et al, 2001;Song et al, 2001). However, the molecular mechanism of estrogen signaling through ER in IGFBP-6 transcription has not been determined.…”

Section: Figurementioning

confidence: 99%

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Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

et al. 2009

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Osteoblasts can synthesize the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs), which may either enhance or attenuate IGF-stimulated bone cell proliferation. Since estrogen induced osteoblastic differentiation and proliferation through an estrogen-responsive gene in target cells, we investigated the effects of estrogen on IGFBP-6 expression in the human osteoblastic-like cell line SaOS-2. Expressions of IGFBP-6 protein and mRNA increased 2.8 and 2-fold, respectively, in the presence of 17-β-estradiol (E2) (0.01 to 1 μM) and estrogen receptor (ER) in SaOS-2 cells. On the other hand, E2 induced a 2-fold increase in SaOS-2 cell proliferation. To identify genomic sequences associated with estrogen responsiveness, the 5'-promoter region (-44 to +118) of the IGFBP-6 gene was cloned into a chloramphenicol acetyltransferase (CAT) reporter vector. E2 induced a 3-fold increase in CAT activity in SaOS-2 cells transiently transfected with this construct. Identification of the estrogen-responsive element (ERE) [5'-CCTTCA CCTG-3'] (-9 to +1) in this IGFBP-6 gene promoter region was confirmed using electromobility shift assays and deletion analysis. This functional ERE was important for E2-induced trans-activation of the IGFBP-6 gene.These results demonstrate that E2 exhibits a positive effect on IGFBP-6 gene transcription through estrogen-liganded ER binding to the functional ERE in the IGFBP-6 gene promoter in SaOS-2 cells.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

et al. 2009

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“…ACAT1 has been shown to be present in most tissues, whereas the location of ACAT2 has been relatively unclear. According to previous studies (4)(5)(6), ACAT2 is found mainly in the apical region of the intestinal villi and in human fetal liver, whereas ACAT1 is the major ACAT isoenzyme in adult human liver. However, we recently showed that ACAT2 is the major ACAT isoenzyme in adult human liver and that it is located in hepatocytes, whereas ACAT1 is located in Kupffer cells (7).…”

mentioning

confidence: 86%

“…To investigate the hepatocyte and promoter specificity of these findings, we transfected the human kidney cell line HEK293, which does not express ACAT2 (6), with the same ACAT2 promoter constructs described above. HEK293 cells displayed Ͼ20-fold lower luciferase activity than HepG2 Fig.…”

Section: Cloning and Identification Of Cis-acting Elementsmentioning

confidence: 99%

Control of ACAT2 liver expression by HNF1

Pramfalk

Davis

Eriksson

et al. 2005

Journal of Lipid Research

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ACAT catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acids. There are two known genes encoding the two ACAT enzymes, ACAT1 and ACAT2 (also known as Soat1 and Soat2). In adult humans, ACAT1 is present in most tissues, whereas ACAT2 is localized to enterocytes and hepatocytes. In this report, we elucidate the mechanisms that control the liver-specific expression of the human ACAT2 gene. We identified hepatic nuclear factor 1 (HNF1) as an important liver-specific transacting element for the human ACAT2 gene using the human hepatocellular carcinoma cell lines HuH7 and HepG2. Tar ACAT is an integral membrane protein of the rough endoplasmic reticulum that catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acids (1). The solubility characteristics of cholesteryl esters make them the major choice for the storage of cholesterol, mostly as cytoplasmic lipid droplets inside the cells. Thus, ACAT is a key enzyme in the control of intracellular cholesterol storage and in determining the level of free cholesterol (2). There are two known genes that encode the two ACAT enzymes, ACAT1 and ACAT2, also known by international convention as steroyl O -acyltransferase (i.e., Soat1 and Soat2, respectively) (3). ACAT1 has been shown to be present in most tissues, whereas the location of ACAT2 has been relatively unclear. According to previous studies (4-6), ACAT2 is found mainly in the apical region of the intestinal villi and in human fetal liver, whereas ACAT1 is the major ACAT isoenzyme in adult human liver. However, we recently showed that ACAT2 is the major ACAT isoenzyme in adult human liver and that it is located in hepatocytes, whereas ACAT1 is located in Kupffer cells (7). This is consistent with similar findings in mice and nonhuman primates (8,9) and is also in agreement with the proposed role for ACAT2 in the assembly and secretion of cholesteryl esters in lipoproteins.Based on this new knowledge, ACAT2 may be a viable target for the treatment and prevention of diseases associated with cholesterol accumulation (e.g., atherosclerosis). Thus, it is of great importance to characterize the mechanisms involved in ACAT2 transcriptional regulation. In the present study, we identify an important liver-specific cis -acting element in the promoter region of ACAT2 that acts as a putative binding site for the hepatic nuclear factor 1 (HNF1). This element serves as a positive regulator of gene expression and is functionally active. Finally, by chromatin immunoprecipitation assay, we show that the transcription factors HNF1 ␣ and HNF1 ␤ bind to the identified promoter region of ACAT2 in vivo in human liver.

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“…Anti-human ACAT1, anti-p65 and anti-p50 polyclonal antibodies were from Santa Cruz Biotechnology (Santa Cruz, USA). Anti-human ACAT2 polyclonal antibodies were generated by immunizing rabbits followed by affinity purification with antigen (22). SYBR Green I and Trizol total RNA extraction kit was purchased from Invitrogen (Carlsbad, USA).…”

Section: Reagentsmentioning

confidence: 99%

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

Lei

Xiong

Chen

et al. 2009

Journal of Lipid Research

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High levels of the inflammatory cytokine tumor necrosis factor-a (TNF-a) are present in atherosclerotic lesions. TNF-a regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-a may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-a enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-a. Our data demonstrate that TNF-a, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF-a is proatherosclerotic during early phase of lesion development.-Lei, L., Y.

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Organization of Human ACAT-2 Gene and Its Cell-Type-Specific Promoter Activity

Cited by 25 publications

References 47 publications

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

Control of ACAT2 liver expression by HNF1

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

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