Members of the Caudal Family of Homeodomain Proteins Repress Transcription from the Human Apolipoprotein B Promoter in Intestinal Cells

Abstract

Apolipoprotein B (apoB) is the major protein component of low density lipoproteins, and plays a central role in cholesterol transport and metabolism. The apoB gene is transcribed in the liver and in the intestine in humans. Although much is known about the DNA sequence elements and protein factors that are important for transcription of the human apolipoprotein B gene in the liver, less is known about the mechanisms that control transcription of this gene in the intestine. The sucrose isomaltase gene (SI), is expressed exclusively in the intestine. Two sequences from the promoter region of the SI gene, namely SIF-1 and SIF-3, are essential for promoter activity of the SI gene in intestinal cells. Sequences displaying a high degree of similarity to those of SIF-1 and SIF-3 are present in the third intron of the apoB gene. Rather than stimulating apoB promoter activity, the BSIF-1 and BSIF-3 sequences repressed transcription in CaCo-2 cells. Gel retardation studies demonstrated that BSIF-1, like SIF-1, binds to proteins related to the caudal family of proteins such as mCdx-4 and mCdx-2. These proteins appear to repress transcription from the apoB promoter by a mechanism that involves an interaction with members of the C/EBP family of proteins, that bind to a target sequence for the repressor in the segment from ؊139 to ؊111 of the apoB promoter. On the other hand, BSIF-3, like SIF-3, binds to HNF-1 and also represses transcription from the apoB promoter.In recent years, a large body of data has been gathered regarding the mechanisms that operate to control the expression of eucaryotic genes in specific tissues and cell types. One such tissue that has received a lot of attention is the liver. Work in many laboratories studying liver-specific gene expression has revealed that a relatively small number of hepatic transcription factors, acting cooperatively with other ubiquitous transcription factors or synergistically with each other influence transcription of many hepatic-specific genes in cultured cell lines and also in transgenic animals (1-4). Many key liver-specific transcription factors have been identified and their mode of binding and influencing transcription has been characterized for some genes. Thus, HNF-1 1 (5), C/EBP (6), HNF-3 (7) and HNF-4 (8), alone or in combination, appear to play a role in the regulation of transcription of most hepaticspecific genes that have been examined so far, either by binding to the promoter region itself, or to tissue-specific enhancer elements localized upstream or downstream of the transcriptional start site.Apolipoprotein B is the sole protein component of low density lipoprotein and plays an important role in cholesterol homeostasis and coronary artery disease in humans (9). It is encoded by a single-copy gene in the human genome that extends over 48 kilobases and is transcribed mainly in the liver and intestine (10). Work in our laboratory and in others has defined the cis-acting DNA sequences and the trans-acting protein factors involved in the transcriptional contro...

The Private Hepatocyte Nuclear Factor-1α G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree

“…The normal actions of HNF-1␣ include enhancing the transcription of apo B [23][24][25] and suppressing the transcription of apo AI. 27 Thus, in subjects with type 2 diabetes, the lower plasma total and LDL cholesterol and apo B levels would also be consistent with transactivational loss of function of the HNF1A S319 product.…”

“…20 -22 The HNF1A gene product, HNF-1␣, is a transcriptional activator of several hepatic genes, including albumin, ␣1-antitrypsin, and ␣-and ␤-fibrinogen. 21,22 In addition, HNF-1␣ was shown to enhance transcription of apolipoprotein (apo) B [23][24][25] and apo(a) 26 and to downregulate transcription of apo CIII and apo AI. 27 Because it regulates the transcription of several apolipoprotein genes, it is possible that naturally occurring mutations in HNF-1␣ could affect plasma lipoprotein metabolism.…”

The Nuclear Matrix Protein CDP Represses Hepatic Transcription of the Human Cholesterol-7α Hydroxylase Gene

“…Gel Retardation Assays-COS cells were transfected (as described above) with 10 g of expression plasmids for either CDP (pMT2.CDP), C/EBP-␣ (pMSV.C/EBP␣), or HNF-1␣ (pGEM.HNF-1␣), and cellular lysates enriched for these proteins were prepared as described previously (20). Binding sites for transcription factors CDP, HNF-1␣, and C/EBP␣ were identified within CYP7A1 intron 1, using the online TRANSFAC 3.5 data base sequence search and analysis service (21).…”

Differential Regulation of Basal and Cyclic Adenosine 3',5'-Monophosphate-Induced Somatostatin Gene Transcription in Neural Cells by DNA Control Elements That Bind Homeodomain Proteins

“…It remains to be determined whether homeodomain transcription factors that recognize TAAT elements in neural cells act as transrepressor proteins or whether they act as transactivators that compete for binding to the same elements with nonhomeodomain-type repressor proteins. Although many homeodomain transcription factors function as transactivator proteins to stimulate transcription of target genes, it has been shown that a number of homeodomain proteins act as transcriptional repressors on the promoter of neural (40)(41)(42)(43)(44)(45) as well as nonneural genes (46)(47)(48). Evidence indicates that these proteins are composed of modular domains, some of which mediate activation whereas others mediate repression (46,(49)(50)(51).…”