NF-IL6β regulates gene expression and plays function roles in many tissues. The EGF-regulated cyclooxygenase-2 (cox-2) expression is mediated through p38MAPK signaling pathway and positively correlates with NF-IL6β expression in A431 cells. NF-IL6β coordinated with c-Jun on cox-2 transcriptional activation by reporter and small interfering RNA assays. NF-IL6β could directly bind to CCAAT/enhancer-binding protein (C/EBP) and cyclic AMP-response element (CRE) sites of the cox-2 promoter by in vitro-DNA binding assay. The C/EBP site was important for basal and, to a lesser extent, for EGF-regulated cox-2 transcription, while the CRE site was a more specific response to EGF inducibility of cox-2 gene. SUMO1 expression attenuated EGF- and NF-IL6β-induced cox-2 promoter activities. NF-IL6β was found to be sumoylated by in vivo- and in vitro-sumoylation assays, and the SUMO1-NF-IL6β (suNF-IL6β) lost its ability to interact with p300 in in vitro-binding assay. NF-IL6β was also acetylated by p300, and acetylation of NF-IL6β enhanced the cox-2 promoter activity stimulated by NF-IL6β itself. In vivo-DNA binding assay demonstrated that EGF stimulated the recruitment of p300 and NF-IL6β to the cox-2 promoter, yet promoted the dissociation of SUMO1-modificated proteins from the promoter. These results indicated that NF-IL6β plays a pivotal role in the regulation of basal and EGF-induced cox-2 transcription.
CCAAT/Enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptors gamma (PPARG) play critical roles in the regulation of lipid metabolism genes. Overexpression of CEBPdelta (CEBPD) enhances lipid accumulation and specifically activates PPARG2 transcription in HepG2 cells. By using 5'-serial deletion reporter analysis, we show that the region comprising the -457 to +129 base pairs is required for CEBPD response of the PPARG2 promoter. Two critical CEBPD-binding motifs on the -324/-311 and -158/-145 of human PPARG2 promoter are identified. We previously have shown that the human CEBPD is sumoylated by small ubiquitin-related modifier-1 (SUMO1). We further demonstrated that the sumoylation of CEBPD lysine 120 is also detectable in HepG2 cells, and this modification functions for binding of the recruits, HDAC1 and HDAC3. Meanwhile, an in vivo chromatin IP assay demonstrated that the sumoylation mutant of CEBPD lost a significant portion of HDAC1 and HDAC3 interaction. Combining that the increasing amount of CEBPD and the sumoylated CEBPD (suCEBPD) consistently responded to lipogenic stimulation, these results suggest that the excess non-sumoylated CEBPD could be a critical activator which reverses suCEBPD/HDAC1/HDAC3-mediated PPARG2 gene inactivation and promotes hepatic lipogenesis. Taken together, we suggest that suCEBPD/HDAC1/HDAC3 complex inactivates PPARG2 transcription, and the induction of CEBPD expression transiently activates PPARG2 transcription which is involved in adipocyte-like lipogenesis in HepG2 cells.
Hypoxia-inducible factor (HIF) accumulates when tumors grow under hypoxic conditions. The genesis of tumors, however, usually involves normoxic conditions. In this study, we were interested in examining the potential role of aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF-1 in tumor growth under normoxic conditions, specifically when cells are treated with epidermal growth factor (EGF), which is known to affect the gene expression of tumor growth-related protein COX-2 (cyclooxygenase-2). The results showed that EGF receptor inhibitor, AG1478, abolished EGF-induced nuclear accumulation of ARNT as well as the expression of COX-2. ARNT small interfering RNA inhibited the promoter activity, mRNA level, and protein expression of COX-2 in cells treated with EGF. In contrast, CoCl 2 -induced HIF-1␣ exhibited no effect on COX-2 expression. EGF also stimulated the formation of the ARNT⅐c-Jun complex as well as the complex binding to the COX-2 promoter. ARNT small interfering RNAs blocked EGF-activated cell migration. Moreover, COX-2 and ARNT were cohorts present distinctively in clinical specimens of human cervical squamous cell carcinoma and were almost nondetectable in adjacent normal or noncancerous cervical tissues. Our results revealed that ARNT plays an important role in EGF-regulated COX-2 gene expression and may thus be related to either a cause or a consequence of tumorigenesis in cervical cancer.The aryl hydrocarbon receptor nuclear translocator (ARNT) 3 (also known as HIF-1 (hypoxia-inducible factor-1)) is a member of the basic helix-loop-helix Per/aryl hydrocarbon receptor (AhR)/ARNT/Sim (bHLH-PAS) family of transcription factors and a general partner factor for bHLH-PAS proteins such as the AhR, HIF-1␣ (hypoxia-inducible factor-1␣), and single-minded (SIM) proteins (1). Although the in vivo importance of ARNT homodimers remains unclear, each of the heterodimeric ARNT-containing complexes plays a critical function in pathways used to respond to environmental conditions. As in exposure to xenobiotic compounds, the AhR/ ARNT heterodimer recognizes and promotes transcription from xenobiotic response elements found upstream of 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive genes (1). ARNT also cooperates with HIF-1␣ to form a heterodimer and regulates several genes involved in tumorigenesis under hypoxia (2). In addition, ARNT is essential for normal embryonic development (3). Loss of ARNT results in reduced tumor growth, decreased angiogenesis, and increased response to radiotherapy (4, 5). Inactivation of ARNT suppresses the development of liver hemangioma, polycythemia, and HIF-induced gene expression. Unlike ARNT, however, HIF-1␣ is insufficient to suppress the development of the Von Hippel-Lindau-associated polychthemia (6). These results demonstrate that the development of Von Hippel-Lindau-associated vascular tumors in the liver depends on functional ARNT but not in an HIF-1␣/hypoxia-dependent manner. Prostaglandin endoperoxide synthase, also known as cyclooxygenase, plays a regulatory role in...
Epithelial-mesenchymal transition (EMT) is a developmental program that is associated with esophageal squamous cell carcinoma (ESCC) progression and metastasis. Recently, C/EBPb has been reported to be an EMT inducer in cancer. However, the detailed molecular mechanisms remain unclear. Here, we report for the first time, that the truncated CCAAT-enhancer-binding protein b (C/EBPb) LIP isoform is abnormally overexpressed and correlated with cancer metastasis in clinical specimens of human ESCC. Furthermore, we demonstrate that C/EBPb LIP mediates epithelial growth factor (EGF)-induced EMT and increases migration and invasion of esophageal cancer cells in a manner that is dependent on miR-203 inactivation. Finally, we identified miR-203 as a direct target of C/EBPb LIP. Disruption of C/EBPb LIP attenuated the EGF-mediated decrease in miR-203, whereas overexpression of C/ EBPb LIP alone markedly suppressed miR-203. In addition, we demonstrated that C/EBPb LIP inhibited miR-203 transcription by directly interacting with a conserved distal regulatory element upstream of the miR-203 locus, and in doing so, orchestrated chromatin remodeling. In conclusion, our results have revealed a new regulatory mechanism that involves C/EBPb-LIP-mediated downregulation of miR-203, which plays a key role in EMT and metastasis.
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