pS2Gene Expression in HepG2 cells: Complex Regulation through Crosstalk between the Estrogen Receptor α, an Estrogen-Responsive Element, and the Activator Protein 1 Response Element

Abstract

The pS2 promoter is complex with binding sites for a number of protein factors that may participate in modulating its activity. The pS2 gene was transcriptionally activated by estrogens in HepG2 cells transformed (HepER3) to express the estrogen receptor ␣ (ER␣). The phorbol ester phorbol 12-myristate 13-acetate (PMA) stimulated pS2 expression in both HepER3 and the parental, non-ER-expressing HepG2 cells, although its activity was substantially less in HepG2 cells. The use of selective protein kinase inhibitors suggested that the MAPK pathway contributes substantially to estrogen stimulation of the pS2 promoter. The activator protein 1 (AP1) site at Ϫ332 to Ϫ338 in the pS2 promoter had a dominant role in the response to both estrogens and PMA, although the estrogen response element at Ϫ393 to Ϫ405 was essential to mediate the response to estrogen. The potentiation of pS2 promoter activity by the AP1 motif in response to estrogen was dependent on the ligand binding domain of ER␣. Furthermore, the presence of an intact AP1 element in the pS2 promoter sustained suppression of pS2 promoter activity by an LXXLL peptide. In summary, the data suggest that the effect of estrogen is mediated through a cross-talk between the estrogen-responsive element and the AP1 response element and that ER␣ plays a crucial role in mediating the effect of both estrogen and PMA.

Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas

“…activation of the TFF1 promoter (16). Binding between c-Jun and ERa was shown by mammalian two-hybrid assay and was independent of ER binding to DNA (24), and mutation of a conserved lysine on ERa results in hyperstimulated AP-1 activation of gene promoters (25), further supporting a direct interaction between ER and AP-1.…”

“…3A). The mutants serially eliminated consensus-binding sites of transcription factors that were known to alter TFF1 expression (7,16,20,21). Transient transfection of AGS gastric adenocarcinoma cells was followed by luciferase assays.…”

“…Recent data indicate that estrogen response element is dominant in stimulating TFF1 expression in breast cancer cells (15). Similarly, the importance of estrogen stimulation in induction of TFF1 expression was observed in hepatic cancers (16), although cross-talk between multiple pathways seems to be involved.…”

Genomic actions of estrogen receptor α: what are the targets and how are they regulated?

“…The transcription factor AP-1 is a complex containing fos, jun, and other family members. Several E 2 -regulated genes are dependent on AP-1, such as insulin-like growth factor I (IGF-I), ovalbumin, progesterone receptor, and pS2/TFF1 (Gaub et al 1990, Savouret et al 1994, Umayahara et al 1994, Barkhem et al 2002. The AP-1 complex binds to promoters of genes involved in growth, differentiation, and development.…”

Tamoxifen accelerates proteasomal degradation of O6‐methylguanine DNA methyltransferase in human cancer cells

“…For this purpose, we chose two ER-positive cells, including breast carcinoma MCF-7 27 and BT-474, 28 and 4 ERnegative cells, including HT-29 (colorectal carcinoma), 27 A375 (melanoma), 29 Hep G2 (hepatocellular carcinoma) 30 and H460 (nonsmall cell lung cancer) 31 on this study. As shown in Figure 3b, tamoxifen was able to decrease MGMT protein levels in both ER-negative (HT-29, A375, Hep G2 and H460) and ER-positive (MCF-7 and BT-474) cells (Fig.…”