Differential Regulation of Two Alternatively Spliced Isoforms of Hypoxia-inducible Factor-1α in Activated T Lymphocytes

Abstract

Cell adaptation to hypoxia is partially accomplished by hypoxia-inducible transcription factor-1 (HIF-1). Here we report the hypoxia-independent up-regulation of HIF-1α subunit in antigen receptor-activated T cells. This is explained by a selective up-regullation of alternatively spliced mRNA isoform I.1 that encodes the HIF-1α protein without the first 12 N-terminal amino acids. We show that both short (I.1) and long (I.2) HIF-1α isoforms display similar DNA binding and transcriptional activities. Major differences were observed between these two HIF-1α isoforms in their expression patterns with respect to the resting and activated T lymphocytes in hypoxic and normoxic conditions. The T cell antigen receptor (TCR)-triggered activation of normal ex vivo T cells and differentiated T cells results in up-regulation of expression of I.1 isoform of HIF-1α mRNA without an effect on constitutive I.2 HIF-1α mRNA expression. The accumulation of I.1 HIF-1α mRNA isoform in T lymphocytes is also demonstrated during cytokine-mediated inflammation in vivo, suggesting a physiological role of short HIF-1α isoform in activated lymphocytes. The TCR-triggered, protein kinase C and Ca2+/calcineurin-mediated HIF-1α I.1 mRNA induction is protein synthesis-independent, suggesting that the HIF-1α I.1 gene is expressed as an immediate early response gene. Therefore, these data predict a different physiological role of short and long isoforms of HIF-1α in resting and activated cells.