Copper is an essential micronutrient for cell growth but is toxic in excess. Copper transporter (Ctr1) plays an important role in regulating adequate copper levels in mammalian cells. We have shown previously that expression of the human high-affinity copper transporter (hCtr1) was transcriptionally up-regulated under copper-depleted conditions and downregulated under replete conditions; moreover, elevated hCtr1 levels suppress hCtr1 expression. Specificity protein 1 (Sp1) regulates expression of hCtr1 under copper-stressed conditions. In this study, we made the following important observations: 1) Sp1 expression is down-regulated under copper-replete conditions but up-regulated under copperdepleted conditions. These up-and down-regulations of Sp1 in turn regulate hCtr1 expression to control copper homeostasis. 2) Copper-regulated Sp1 expression involved Sp1 binding to its own promoter as demonstrated by the chromatin immunoprecipitation assay; therefore, Sp1 is also transcriptionally self-regulated via hCtr1/copper intermediation. 3) Both zinc finger and glutamine-rich transactivation domains of Sp1 are involved in the Sp1-mediated hCtr1 and Sp1 regulation by copper stresses. 4) Although Sp3 expression is also regulated by copper availability, Sp3 does not regulate hCtr1 homeostasis. Collectively, our results demonstrated that mammalian cells use Sp1 oscillation in response to copper availability to regulate copper homeostasis through hCtr1 expression in a tripartite inter-regulatory relationship. These findings have important implications in mammalian copper physiology regulation.
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...
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