Until now, it is known that hypoxia increases the glycolytic enzyme expression at the transcriptional level. Here, we show evidence that hypoxia increases hepatic glucose output and HIF-1 and ATF-2-mediated transactivation of phosphoenolpyruvate carboxykinase (PEPCK), which plays a critical role as a rate-limiting enzyme in gluconeogenesis, gene in liver. HIF-1 directly bound to the specific PEPCK promoter region through its cognate binding element and found as an active complex with coactivator CBP. Additionally, ATF-2 was also involved to regulate hypoxia-dependent PEPCK transcription in the transcriptional complex with HIF-1 and CBP. Interestingly, retinoic acid (RA) signaling induced the recruitment of HIF-1 on the PEPCK promoter, resulting from the functional interaction of HIF-1 and ATF-2 with coactivator CBP. Taken together, these results suggest that hypoxia signaling leads the hepatic glucose production and release via the increased gene expression of gluconeogenic enzymes, possibly playing a role in providing glucose to other tissues, such as endothelial, brain and muscle cells.

Small heterodimer partner (SHP) is an atypical member of nuclear receptor superfamily that lacks a DNA binding domain. Here, we show that SHP expression increases during monocytic differentiaton with exposure HL-60 leukemia cells to a 12-O-tetradecanoylphorbol-13-acetate (TPA) response element, whose treatment induced the SHP promoter activity dependent on c-Jun expression, which is well known to be involved in the commitment step in the TPA-induced differentiation of HL-60 leukemia cells. We also show that overexpression and activation signaling of c-Jun increase the SHP promoter activity, suggesting that the level of SHP expression is normally limiting for c-Jun-dependent monocytic differentiation. Electrophoretic mobility shift assays using oligonucleotides derived from the SHP promoter reveal that c-Jun exhibit TPA-induced DNA binding, providing a mechanism for the transcriptional activation of SHP gene expression. It was also found that overexpression of SHP and c-Jun greatly facilitated monocytic differentiation by TPA and surprisingly, that expression of SHP or c-Jun alone was sufficient to make cells differentiate into functionally mature monocytes, but silencing of SHP and c-Jun by RNA interference diminished the TPA-induced monocytic differentiation. Taken together, these works suggest that c-Jun works to activate the expression of SHP genes associated with the cascade regulation of monocytic differentiation.