Cyclin dependent kinase inhibitor p27Kip1 is upregulated by hypoxia via an ARNT dependent pathway

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Abstract
Expression of cyclin dependent kinase (Cdk) inhibitor p27Kip1, which blocks cell cycle progression from G1 to S phase, can be regulated via multiple mechanisms including transcription, protein degradation, and translation. Recently, it was shown that p27Kip1 plays an important role in the cellular response to hypoxia. However, the mechanisms involved in the hypoxia‐induced regulation of p27Kip1 expression are still not clear. In this study, we compare the expression of p27Kip1 in two related murine hepatoma cell lines, Hepa‐1 and c4. Hepa‐1 produces functional aryl hydrocarbon receptor nuclear translocator (ARNT). c4 cells are derived from Hepa‐1, but are ARNT deficient. Interestingly, we observed cell line‐dependent effects of hypoxia on the expression of p27Kip1. The level of p27Kip1 protein in Hepa‐1 cells is enhanced by hypoxia, but is reduced by hypoxia in c4 cells. Further investigation demonstrated that hypoxia‐induced, ARNT‐mediated, transactivation of the p27Kip1 gene in Hepa‐1 cells is responsible for the increase in p27Kip1 protein. Once c4 cells were stably transfected with the wild type ARNT gene, a hypoxia‐induced increase in p27Kip1 mRNA was observed and reduction of p27Kip1 protein caused by hypoxia was blocked. Hence, our data indicate that ARNT is involved in transcriptional upregulation of the p27Kip1 gene under hypoxic conditions.