Interactions between HIF-1 and Jab1: balancing apoptosis and adaptation. Outline of a working hypothesis

When cells experience hypoxia, they either die by apoptosis or adapt to the hypoxic conditions by a series of compensatory mechanisms. Hypoxia inducible factor-1 (HIF-1) is a transcription factor involved in both processes, but the exact mechanisms regulating whether the cells survive (adapt) or perish by apoptosis are largely unknown. We hypothesize that the balancing between apoptosis and adaptation is governed by a triangular feedback system involving the alpha-subunit of HIF-1, p53, and jun activating binding protein 1 (Jab1). Jab1 and p53 bind competitively to the same domain on HIF-1alpha resulting in either stabilization or degradation of HIF-1alpha, respectively. Moreover, p53 is stabilized by binding to HIF-1alpha, whereas its interaction with Jab1 targets p53 for degradation. Thus as a consequence we propose that the ratio between p53 and Jab1 determine whether a hypoxic induction of HIF-1 results in apoptosis or adaptation, with Jab1 as the factor promoting adaptation. On this background we consider Jab1 an interesting molecular target for anticancer therapy.