| Summary: | 碩士 === 國立成功大學 === 藥理學研究所 === 98 === The aryl hydrocarbon receptor nuclear translocator (ARNT), also known as HIF-1β, belongs to the bHLH/PAS family of transcription factors and is a general partner for other bHLH/PAS proteins such as AhR, HIF-1α, and SIM proteins. Previous studies had shown that ARNT functions as a central axis in the gene expression networks of many essential physiological processes (e.g., in response to hypoxia, xenobiotics, and in neural development). Our previous studies have shown that ARNT is involved in EGF-induced COX-2 expression in normoxia, indicating its tumorigenesis role in normoxia. Also, comparison of ARNT expression between normal cells and tumor cells demonstrated that aberrantly expressing of ARNT in tumor cells, implying its proliferative advantage. Recently, the emerging roles of ARNT in cell cycle regulation are gradually elucidated. For example, ARNT is involved in the cell cycle regulation in response to hypoxia and xenobiotics. However, the functional role of ARNT within cell cycle progression in normoxia remains unknown. Our preliminary results illustrated that the absence of ARNT in HeLa cells resulted in inhibition of cell proliferation. In addition, by using immunofluorescence assay, less BrdU incorporation was observed in ARNT knockdown cells, indicating a potential role of ARNT in G1/S transition. Therefore, we further investigated which cyclins, e.g., cyclin D1 and cyclin E play vital roles in the regulating ARNT-mediated cell cycle progression. ARNT small interfering RNA-treated HeLa cells showed decreased expression of cyclin E, whereas cyclin D1 expression was increased. However, we found that cyclin E mRNA level was not changed in ARNT knockdown cells, suggesting cyclin E was regulated by ARNT only at the translation level. Furthermore, cell cycle progression analysis by flow cytometry showed that absence of ARNT resulted in the retardation of S phase progression. Taken together, these results suggest that knockdown of ARNT leads to upregulation of cyclin D1 and downregulation of cyclin E, which at least partially contributes to the S phase retardation. These findings suggested a possible role of ARNT that it may participate in the tumorigenesis through the regulation of cell cycle progression in normoxia.
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