Tight Control of Hypoxia-inducible Factor-α Transient Dynamics Is Essential for Cell Survival in Hypoxia

Abstract

Background: Hypoxia inducible factor-α (HIF-α) is the main transcription factor activated in low oxygen conditions.Results: Single cell imaging reveals pulses in nuclear levels of HIF-α.Conclusion: The transient nature of the HIF-α nuclear accumulation is required to avoid cell death.Significance: The duration of HIF-α response depends on cellular oxygenation, and can encode information and dictate cell fate.

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…This observation is further supported by doseresponse simulations showing that the steady-state level of HIF-1 exponentially depends on the PHD2 mediated feedback strength while it is relatively insensitive to change in feedback strength mediated by PHD3 ( Figure 2F). These simulations are in agreement with the conclusions in previous reports suggesting PHD2 to be the more dominant isoform in driving HIF-1 transient response [34,35]. Further questions could be asked.…”

“…Yet, the fact that both PHD2 and PHD3 form negative feedback loops with HIF-1 posed questions of whether they are functionally redundant, and if not, how different are individual isoforms in modulating HIF timing, duration and signaling amplitude? To probe these questions, we adapted a model recently developed by Bagnall et al which was trained using single-cell imaging data of HIF dynamic profiles [34]. The schematic diagram of this model is given in Figure 2A, and detailed model information is presented in the Supplementary Materials (SM).…”

Computational analysis of signaling patterns in single cells

“…Human signaling proteins show a wide range of dynamical behaviors including pulses [13, 18, 23], bursts [14], oscillations [24], switches [25], and decays [26]. One of the best-studied proteins in single cells is the stress response factor NF-κB.…”

“…We first introduce some of the different patterns of signaling observed in individual cells across different cellular pathways. Since this topic has been reviewed elsewhere in depth [11, 12], we provide a brief overview of the variety of signaling patterns observed among mammalian proteins and highlight the insight gained from an exciting set of recent studies [1, 13–18]. These studies are drawn together by a common set of computational approaches used to analyze signaling patterns in individual cells.…”

The Role of Hypoxia-Inducible Factor-1α in Response to Injury and Hypoxia*

“…This article joins the growing body of literature demonstrating that hypoxia-inducible factor (H IF)-la is a significant contributor to the cellular signaling pathways that are involved in the body's adaptive response to hypoxia (2-4). Posttranslational modifi cations of this oxygen-sensitive transcription factor have been demonstrated to be involved in hypoxia-induced apoptosis (5) and the cell's ability to survive in hypoxia-associated con ditions (6). Furthermore, due to the purported role of HIFl a in tumor growth and angiogenesis (7), polymorphisms in H IF -la genotypes have been proposed to be associated with an increased risk of a variety of malignancies, including lung cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, multiple myeloma, and head and neck cancer (8)(9)(10)(11).…”