Functional analysis of basic transcription element (BTE)-binding protein (BTEB) 3 and BTEB4, a novel Sp1-like protein, reveals a subfamily of transcriptional repressors for the BTE site of the cytochrome P4501A1 gene promoter

Abstract

The Sp1-like family of transcription factors is emerging as an integral part of the cellular machinery involved in the control of gene expression. Members of this family of proteins contain three highly homologous C-terminal zinc-finger motifs that bind GC-rich sequences found in the promoters of a diverse number of genes, such as the basic transcription element (BTE) in the promoter of the carcinogen-metabolizing cytochrome P4501A1 (CYP1A1) gene. In the present study, we report the molecular and functional characterization of BTE-binding protein (BTEB) 4, a novel ubiquitously expressed member of the Sp1-like proteins family. This protein represents a new homologue of BTEB1, originally described as a regulator of the BTE site in the CYP1A1 gene promoter. Similarly to the recently described BTEB3, we demonstrate that the N-terminal region of BTEB4 directly represses transcription and binds the co-repressor mSin3A. In addition, we show that the C-terminal zinc-finger domain of BTEB4 binds specifically the BTE site of the CYP1A1 promoter, similar to BTEB1 and BTEB3. Also, we show that both BTEB3 and BTEB4 repress the CYP1A1 gene promoter via the BTE site in HepG2 and BxPC3 cells. Thus the identification of this protein expands the repertoire of BTEB-like members of the Sp1-like protein family involved in transcriptional repression. Furthermore, our results demonstrate that the BTEB subfamily can repress the CYP1A1 gene promoter via the BTE site.

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

“…14 In fact, it is widely reported that different members of the KLF family may compete for the consensus sites of the promoter regions, perhaps due to similarity in their recognition sequences. [33][34][35][36][37] For example, KLF5 could abrogate the activating effect of KLF4 on the Klf4 promoter, whereas KLF4 could abrogate the inhibiting effect of KLF5 on the same promoter, and it was speculated that this competing effect was due to physical competition of the two proteins for binding to a cognate DNA sequence. 36 In another report, KLF9 competed with Sp1 for the BTE sequence in the cytochrome P4501A1 promoter.…”

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

“…It was shown that the bHLH-PAS domains of the AhR/ARNT complex interact with the Sp1 zinc finger motif (Kobayashi et al, 1996). In contrast, a repressive role in the regulation of CYP1A1 was reported for the GC-box binding, Sp1-related transcription factors basic transcription element binding 3, basic transcription element binding 4, and gut-enriched Krüppel-like factor (Imataka et al, 1992;Zhang et al, 1998;Kaczynski et al, 2002). The observed up-regulation of CYP1A1 by MitA may be either due to interference with the GC-box in the AhRR enhancer region and a consequentially decreasing AhRR synthesis or to a displacement of repressive-acting Sp-like molecules from the CYP1A1 enhancer.…”

Characterization of the Human Lung CYP2F1 Gene and Identification of a Novel Lung-specific Binding Motif

“…Overlapping a C/EBP site, a basic transcription element (BTE) was identified. A BTE site in the promoter of the carcinogen-metabolizing CYP1A1 gene has been demonstrated to control the pulmonary specific regulation of CYP1A1 (35,36). In addition, several elements that have been implicated in regulating constitutive gene expression were also identified (Sp1 and AP2).…”

“…A 1.3-kbp sequence from the CYP2B promoter was shown to drive lung-specific reporter gene expression in a transgenic mice, and it was shown that C/EBP␣ and C/EBP␦ regulate CYP2B pulmonary expression during differentiation (19). In addition, the promoter contains a BTE site that has been demonstrated in numerous studies (35,36,47) to regulate CYP1A1 transcription. The BTE site of CYP1A1 has been recognized to bind a number of transcription factors from the Sp/XKLF family of factors, which are involved in both constitutive and tissuespecific regulation (48).…”