hypoxia-inducible factor-1alpha signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals mediated by hypoxia-inducible factor (HIF1) in response to lowered oxygen levels (hypoxia). Under hypoxic conditions, the oxygen-sensitive alpha-subunit of hypoxia-inducible factor (HIF)-1 dimerizes with a HIF1-beta subunit (also called ARNT or aryl-hydrocarbon-receptor nuclear translocator), translocates to the nucleus and activates transcription of genes whose products participate in responding to hypoxia. [GOC:bf, GOC:jc, http://www.sabiosciences.com/pathway.php?sn=HIF1Alpha_Pathway]

Hypoxia-inducible factor-1alpha (HIF-1α) signaling pathway is a crucial cellular response to low oxygen levels (hypoxia). It orchestrates a complex cascade of events that allow cells to adapt to oxygen deprivation and survive. Here's a detailed breakdown:

1. **Hypoxic Induction:** Under normal oxygen conditions, HIF-1α is constantly synthesized but rapidly degraded by the proteasome. This degradation is mediated by the von Hippel-Lindau (VHL) tumor suppressor protein, which binds to HIF-1α and marks it for ubiquitination. However, when oxygen levels drop, the enzyme prolyl hydroxylase domain (PHD) enzymes, which require oxygen as a cofactor, become inactive. This inactivity prevents the hydroxylation of HIF-1α, a critical step in its ubiquitination. Without hydroxylation, HIF-1α escapes VHL-mediated degradation and accumulates in the cytoplasm.

2. **Nuclear Translocation:** As HIF-1α levels rise, it translocates to the nucleus where it forms a heterodimer with HIF-1β, a constitutively expressed protein. This dimerization creates the functional HIF-1 transcription factor.

3. **Gene Transcription:** The HIF-1 complex binds to specific DNA sequences called hypoxia-responsive elements (HREs) located in the promoter regions of target genes. This binding activates the transcription of a wide array of genes involved in:

* **Erythropoiesis:** Stimulating the production of red blood cells, which carry oxygen throughout the body.
* **Angiogenesis:** Promoting the formation of new blood vessels to deliver oxygen to hypoxic tissues.
* **Glucose Metabolism:** Switching from oxidative phosphorylation (oxygen-dependent energy production) to glycolysis (oxygen-independent energy production).
* **Cell Survival:** Activating anti-apoptotic pathways and promoting cell survival in the face of oxygen deprivation.

4. **Reoxygenation:** When oxygen levels return to normal, PHD enzymes become active again. HIF-1α is hydroxylated, targeted for degradation by the proteasome, and its transcriptional activity is suppressed, restoring normal cellular function.

5. **Dysregulation and Disease:** Dysregulation of the HIF-1α pathway is implicated in various diseases, including:

* **Cancer:** HIF-1α overexpression promotes tumor growth, angiogenesis, and metastasis.
* **Ischemic Diseases:** Chronic hypoxia in heart, brain, and peripheral tissues can lead to tissue damage and organ dysfunction.
* **Anemia:** Disrupted erythropoiesis due to HIF-1α dysfunction can cause anemia.

6. **Therapeutic Targeting:** Understanding the HIF-1α signaling pathway has led to the development of therapeutic strategies for treating various diseases. For example, HIF-1α activators are being investigated for their potential to stimulate erythropoiesis in anemia and to promote angiogenesis in ischemic tissues. Conversely, HIF-1α inhibitors are being explored for their potential to combat tumor growth and metastasis.'
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Proteins (3)

Compounds (70)