What is the Difference Between HIF-1α and HIF-2α

The main difference between HIF-1α and HIF-2α is that HIF-1α regulates glycolysis, whereas HIF-2α regulates lipoprotein metabolism. 

HIF-1α and HIF-2α are two hypoxia-inducible transcription factors. They respond to decreases in oxygen in the cellular environment or hypoxia.   

Key Areas Covered

1. What is HIF-1α
– Definition, Facts, Function
2. What is HIF-2α
– Definition, Facts, Function
3. Similarities Between HIF-1α and HIF-2α
– Outline of Common Features
4. Difference Between HIF-1α and HIF-2α
– Comparison of Key Differences

Key Terms  

HIF-1α, HIF-2α

What is HIF-1α

HIF-1α is a hypoxia-inducible transcription factor encoded by the hypoxia-inducible factor 1 gene. 

Molecular Biology of HIF-1

Oxygen homeostasis of humans and other vertebrates requires adequate oxygen delivery to the body. Hypoxia is the lack of oxygen. The heterodimeric DNA-binding complex, HIF, contains two basic helix-loop-helix proteins in the PAS family. It is formed by the binding of one of the hypoxia-inducible α-subunits, HIF-1α or HIF-2α, to the constitutive HIF-1β. The forming heterodimer binds to the core pentanucleotide sequence (RCGTG) in the hypoxia response elements (HREs) of target genes in hypoxia. However, HIF-β subunits are nuclear proteins that are non-responsive to oxygen but have other roles in transcription. In comparison, HIF-α subunits are the highly inducible proteins by hypoxia.

Figure 1: HIF-1α

Regulation by Protein Hydroxylation

Furthermore, HIF-α subunits have a very short half-life under normal oxygen concentrations. Therefore, the cells continuously synthesize and degrade HIF-α subunits under these conditions. The HIF-α subunit and oxygen undergo enzymatic reactions such as hydroxylation regulating the interactions with the von Hippel–Lindau tumor suppressor protein (pVHL). The pVHL serves as the E3 ubiquitin ligase complex’s recognition component, targeting the proteolysis of HIF-α subunit. The E3 ubiquitin ligase complex’s other components are elongin B, elongin C, Rbx1, and Cul2. 

However, the degradation of the HIF-α subunit retards under decreasing oxygen concentrations. Prolyl hydroxylation suppresses under hypoxic conditions, and HIF-α subunits undergo accumulation. Also, it is translocated to the nucleus, dimerizing with the HIF-1β subunit. The α/β heterodimer complex then binds to the HRE in the target gene.

HIF Isoforms

Moreover, HIF-1α, HIF-2α, and HIF-3α are the three isoforms of HIF-α subunit. Both HIF-1α and HIF-2α have similar domain architecture. Also, they undergo similar proteolytic regulation. Additionally, they have similar functions. However, the function of the HIF-3α subunit is not known. The alternative splicing of HIF-3α forms an inhibitory PAS domain. 

Metabolic Adaptation of HIF-1α

The HIF system widely operates in most cells. The HIF-1α binds to the genes encoding glycolytic enzymes, including phosphoglycerate kinase-1 and lactate dehydrogenase A. Importantly, glucose metabolism is a very efficient process and is oxygen-dependent. Hypoxia upregulates glucose transporters and gluconeogenesis.  

HIF-1α in Angiogenesis

Oxygen demand is high in rapidly proliferating cells such as embryos and tumors. Therefore, angiogenesis is an important component of growth and development. The HIF-1α directly induces genes such as nitric oxide synthases, angiogenic and vascular growth factors (VEGF), and genes regulating matrix metabolism. 

HIF-1α in Cancer

HIF-1α induces many genes that have higher levels of expression in cancer. It increases glucose metabolism and lactate production and decreases respiration. Therefore, HIF activation is a common feature in cancer. 

What is HIF-2α

HIF-2α is another hypoxia-inducible transcription factor encoded by endothelial PAS domain protein 1. In hypoxia, it regulates the lipoprotein metabolism.

Figure 2: Cells Sense and Adaptation to Oxygen Availability 

Similarities Between HIF-1α and HIF-2α

• HIF-1α and HIF-2α are two hypoxia-inducible transcription factors.
• They respond to oxygen concentration in the cellular environment or hypoxia. 

Difference Between HIF-1α and HIF-2α

Definition

HIF-1α refers to the master transcriptional regulator of cellular and developmental response to hypoxia. In contrast, HIF-2α refers to the transcription factors that respond to decreases in available oxygen in the cellular environment.

Gene

HIF-1α is encoded by hypoxia-inducible factor 1, alpha subunit, while HIF-2α is encoded by endothelial PAS domain protein 1.

Metabolism 

HIF-1α regulates glycolysis, while HIF-2α regulates lipoprotein metabolism. 

Conclusion

In brief, HIF-1α and HIF-2α are two hypoxia-inducible transcription factors. They respond to the hypoxia or decreases in oxygen in the cellular environment. HIF-1α is encoded by hypoxia-inducible factor 1. It regulates glycolysis. In comparison, HIF-2α is encoded by endothelial PAS domain protein 1. Also, it regulates the lipoprotein metabolism. Therefore, the main difference between HIF-1α and HIF-2α is their type of metabolism. 

References:

1. Weidemann, A., & Johnson, R. S. (2008, February 15). Biology of hif-1α. Nature News. 

Image Courtesy:

1. “Protein HIF1A PDB 1h2k” By Emw- Own Work (CC-BY SA 3.0) via Commons Wikimedia
2. “HIF Nobel Prize Physiology Medicine 2019 Hegasy ENG” By Dr. Guido Hegasy – Own work (CC BY-SA 3.0) via Commons Wikimedia