Eukaryotic cells sense decreased
oxygen levels and respond by altering their metabolic strategy to sustain non-respiratory
ATP production through glycolysis, and thus promote cell survival in a hypoxic environment.
Protein phosphatase 1 (PP1) has been recently implicated in the governance of the rational use of energy when metabolic substrates are abundant and contributes to cellular recovery following metabolic stress. Under conditions of
hypoxia, the expression of the gamma
isoform of PP1 (PP1gamma), is diminished, an event we have hypothesized to be involved in the adaptive cellular response to
hypoxia. Decreased PP1gamma activity in
hypoxia has a profound impact on the activity of the
cAMP response element binding protein (CREB), a major transcriptional regulator of metabolic genes and processes. Here, we demonstrate a further mechanism leading to inhibition of PP1 activity in
hypoxia which occurs at least in part through increased association with the nuclear inhibitor of PP1 (NIPP1), an event dependent upon decreased basal cAMP/PKA-dependent signaling. Using a dominant negative NIPP1 construct, we provide evidence that NIPP1 plays a major role in the regulation of both
CREB protein expression and CREB-dependent transcription in
hypoxia. Furthermore, we demonstrate functional sequellae of such events including altered gene expression and recovery of cellular
ATP levels. In summary, we demonstrate that interaction with NIPP1 mediates decreased PP1gamma activity in
hypoxia, an event which may constitute an inherent part of the cellular
oxygen-sensing machinery and may play a role in physiologic adaptation to
hypoxia.