Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.

ABSTRACT: Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glyco

SUBMITTER: Wang P 

PROVIDER: S-EPMC11960303 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature