Boolean Network Model of Hypoxia Stress Response Pathway

Abstract

Hypoxic stress is a consequence of the decrease in the oxygen reaching the tissues of the body. The coupling of energy with oxygen makes low tension oxygen sensing and adaptation very essential for survival. The intracellular partial pressure of oxygen is regularly measured by a family of hydroxylase enzymes named as prolyl hydroxylase domain containing proteins (PHD). Hypoxia Inducible Factor (HIF) is the transcription factor that controls the ability of the cell to balance between adaptation and cell death during hypoxia.

During normoxia, HIF1α undergoes non-reversible hydroxylation in the presence of PHD2. The hydroxylated HIF1α interacts with von Hippel-Lindua tumor suppressor protein (pVHL) and is degraded by ubiquitination. During hypoxia, PHD2 is inhibited which results in HIF-1α stabilization. Stabilized HIF-1α enters the nucleus and heterodimerizes with Hypoxia Inducible Factor-1β and the dimeric transcription factor HIF-1 is formed which binds to the response elements of the target genes. HIF-regulated target genes enable cells to induce an adaptive response by increasing glycolysis; angiogenesis etc. or undergo cell death by promoting apoptosis or necrosis.

In this work, a Boolean network is generated whose state transitions realize the hypoxic stress response pathway. The simulated behavior of the Boolean network obtained is consistent with the experimental results from the already published pathway literatures.