Cells are equipped with various mechanisms to adapt to hypoxia (low oxygen), with the transcription factor hypoxia inducible factor 1 alpha (HIF-1 alpha) chief among them. HIF-1 alpha is considered the master transcriptional regulator of cells’ response to hypoxia, inducing transcription of over 60 genes responsible for increasing oxygen delivery or adapting metabolism to hypoxia. These genes include erythropoietin, glucose transporters, glycolytic enzymes, vascular epithelial growth factor (VEGF), and cathepsin D¹.

HIF-1 alpha’s activity is regulated by two separate pathways in the cell, oxygen dependent and independent, which control HIF-1 alpha’s expression, degradation, and transcriptional activity. Dysregulation and overexpression of HIF-1 alpha have been linked to cancer, particularly tumor metabolism and survival: tumor tissue is often hypoxic as the rate of cell proliferation outstrips oxygen availability. HIF-1 alpha’s ability to adapt cell metabolism to hypoxia allows it to optimize tumor development and survival, adapting blood vessel formation and metabolism to hypoxia while promoting metastasis and resisting apoptosis². Regulatory mechanisms exist to resist this: under conditions of a continuing or severe lack of oxygen, other molecules will blunt the response of HIF-1 alpha, resulting in cell death.

What to expect from our poster

The interactive pathway poster explores the oxygen dependent and independent pathways of HIF-1 alpha in both the nucleus and cytoplasm, showing regulation of gene expression, degradation, and transcriptional activity.

The oxygen-dependent pathway

Under normoxic conditions, HIF-1 alpha is constitutively expressed but is rapidly degraded in the cytoplasm. This degradation is prevented under hypoxic conditions, where HIF-1 alpha levels increase substantially.

Cytoplasm oxygen availability is sensed by multiple HIF-1 alpha-specific prolyl hydroxylase (PHD), which hydroxylates HIF-1 alpha under normoxic conditions³. Hydroxylation triggers poly-ubiquitination of HIF-1 alpha, which targets it for degradation by the von Hippel-Linden (pVHL) protein complex, a ubiquitin ligase⁴.

Oxygen levels in the nucleus are detected by asparaginyl hydroxylate factor inhibiting HIF-1 alpha (FIH-1), for which HIF-1 alpha is a substrate. Hydroxylation of HIF-1 alpha by FIH-1 under normoxia prevents interactions between HIF-1 alpha and the p300/CBP (CREB-binding protein) coactivator family, blocking HIF-1 alpha’s transcriptional activity⁵.

Hypoxia leads to substantial upregulation of HIF-1 alpha. Due to the lack of oxygen, hydroxylation of HIF-1 alpha by PHD, occurring under normoxic conditions, is inhibited, which allows HIF-1 alpha to enter the nucleus⁶. FIH-1’s inhibitory hydroxylation in the nucleus is also blocked⁵, so HIF-1 alpha dimerizes with HIF-1 beta and interacts with its coactivators, resulting in the transcription of its target genes.

The oxygen-independent pathway

HIF-1 alpha degradation doesn’t always depend on oxygen presence. In the cytoplasm, heat shock protein 90 (HSP90) competes with the receptor-activated protein C kinase (RACK) over binding to HIF-1 alpha⁷. Binding to HSP90 stabilizes HIF-1 alpha, whereas binding to RACK leads to HIF-1 alpha degradation by a ubiquitin ligase. This mechanism is thought to substantially contribute to determining basal HIF-1 alpha activity in different cell types⁷.

As well as its degradation, HIF-1 alpha’s expression can be regulated independently of oxygen availability. Protein kinase C (PKC) stimulates HIF-1 alpha transcription, working together with phosphoinositol 3-kinase (PI3K), which enhances translation. The P13K pathway mediates the induction of HIF-1 alpha expression by vasoactive hormones and lipopolysaccharides⁶. Transcription of HIF-1 alpha is also controlled by NF- kappa B and p53, with p53 repressing HIF-1 alpha under anoxic conditions, helping to suppress tumor formation⁸.

Finally, HIF-1 alpha’s transcriptional activity can also be regulated oxygen-independently. Sirtuin 1 acts as a redox sensor that regulates HIF-1 alpha activity even during hypoxia. When active, Sirtuin 1 deacetylates HIF-1 alpha, preventing it from interacting with p300 and stopping its transcriptional activity. This action persists even during hypoxia: Sirtuin 1 is dependent on NAD+, which accumulates during low levels of glycolysis, an oxygen-independent process. This interaction allows crosstalk between oxygen- and redox-sensitive pathways in regulating HIF-1 alpha activity⁹.

References

1. Wang, G. L.,, Jiang, B. H.,, Rue, E. A. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceeding of the National Academy of Sciences  92 ,5510-5514 (1995)
2. Muz, B.,, de la Puente, P.,, Azab, F. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckland, N.Z.) , (2015)
3. Salceda, S. &, Caro, J. Hypoxia-inducible Factor 1 Alpha Protein Is Rapidly Degraded by the Ubiquitin-Proteasome System under Normoxic Conditions. Journal of Biological Chemistry  272 ,22642-22647 (1997)
4. Tanimoto, K. Mechanism of regulation of the hypoxia-inducible factor-1alpha by the von Hippel Lindau tumor suppressor protein. The EMBO Journal  19 ,4298-4309 (2000)
5. Dery, M.-A. C.,, Michaud, M. D. &, Richard, D. E. Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. The International Journal of Biochemistry and Cell Biology  37 ,535-540 (2005)
6. Jewell, U. R., et al. Induction of hif-1alpha in response to hypoxia is instantaneous. The FASEB Journal  15 ,1312-1314 (2001)
7. Liu, Y. V., et al. RACK1 competes with hsp90 for binding to HIF-1alpha and is required for O2-independent and hsp90 inhibitor-induced degradation of hif-1alpha. Molecular Cell  25 ,207-217 (2007)
8. Schmid, T.,, Zhou, J., Koehl, R. p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochemical Journal  380 ,289-295 (2004)
9. Lim, J-H.,, Lee, Y-M.,, Chun, Y-S. Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1alpha. Molecular Cell  38 ,864-878 (2010)