Skip global navigation and read the article

Skip global navigation and go to local navigation

Skip global navigation and go to footer navigation



Home  > Frontier Research Unit: Oxygen Biology  > Research Projects

Research Projects

1. Metabolic regulation under hypoxic condition

Hypoxia-Inducible Factor (HIF) is a transcription factor which plays a central role during hypoxic response. HIF-α is actively degraded during normoxic condition, whereas it is stabilized and activated under hypoxic conditions. PHD hydroxylates and regulates the expression of HIF-α. There are three PHDs in mammals; namely PHD1, 2, and 3. We have previously identified that PHD3 forms a complex under hypoxic condition. We recently identified that pyruvate dehydrogenase (PDH) is included in this complex. PDH is an enzyme which converts pyruvate into acetyl CoA, and plays a key role in energy metabolism. We have demonstrated that PDH interacts with PHD3 under hypoxic condition. In PHD3-/- cells, PDH activity is decreased, suggesting that PHD3 positively regulates PDH activity by directly interacting with it. Cancer cells are known to exhibit glycolytic metabolism; however, the molecular mechanism of how such metabolism is formed has not been fully elucidated yet. We aim to understand the mechanism by focusing on the PHD3-PDH interaction.

2. Chronic hypoxic response regulated by CREB signaling pathways

We previously demonstrated that CREB and NF-κB are activated during chronic phase of hypoxia. We now focus on CREB to further elucidate the signaling machinery during chronic hypoxia. Recently, we identified that ER stress response pathway is activated during chronic hypoxia and cross-talks with CREB. Knockdown of CREB in breast cancer cells reduced the expression of two ER stress responsive molecules, PERK and IRE1α, which led to decreased ER stress response in these cells. Consequently, CREB-depleted cells exhibited less tumor metastasis in a tumor mouse model. We are further trying to verify the possibility of CREB to be a therapeutic target for cancer.