Difference Between HIF-1 and HIF-2

The key difference between HIF-1 and HIF-2 is that hypoxia-inducible factor 1 or HIF-1 is the main regulator of responses to hypoxia while HIF-2 is a major determinant factor of invasion and metastasis in various tumours.

Hypoxia is a condition in which tissues do not get enough oxygen. It happens due to an insufficient oxygen concentration in blood. It is a serious condition which can cause several symptoms, including shortness of breath, inability to breathe, headache, confusion or restlessness and possible coma or death. There are hypoxia-inducible factors (HIF). They are transcriptional factors that are heterodimer complexes. They consist of an inducible alpha (α) subunit and constitutively expressed beta (β) subunits. HIF-1, HIF-2 and HIF-3 are three transcriptional factors. Among them, HIF-1 and HIF-2 are regulators of oxygen homeostasis. Both are heterodimeric transcription factors mediating the cellular response to hypoxia.

1. Overview and Key Difference
2. What is HIF-1
3. What is HIF-2
4. Similarities Between HIF-1 and HIF-2
5. Side by Side Comparison – HIF-1 vs HIF-2 in Tabular Form
6. Summary

What is HIF-1?

Hypoxia-inducible factor 1 or HIF-1 is an important transcription factor. It is a heterodimeric molecule composed of an alpha subunit and a beta subunit. It is a basic helix-loop-helix structure. The human HIF1A gene encodes for the alpha subunit. HIF-1 mainly mediates the cellular response to hypoxia. In fact, HIF-1 is a regulator of oxygen homeostasis. It regulates oxygen consumption and morphologically changes in response to varying oxygen concentrations.

Figure 01: HIF-1

In addition to regulating oxygen homeostasis, HIF-1 induces transcription of more than 60 genes, including VEGF, erythropoietin, cell proliferation and survival, as well as glucose and iron metabolism.

What is HIF-2?

HIF-2 is a member of heterodimeric transcription factors that are hypoxia-inducible factors. Similar to HIF-1, HIF-2 is composed of an alpha subunit and beta subunit. Similar to HIF-1, HIF-2 is a regulator of oxygen homeostasis. Moreover, HIF-2 regulates erythropoietin production in adults. In addition, HIF-2 is a major determinant factor of invasion and metastasis in various tumours.

Figure 02: How Cells Sense and Adapt to Oxygen Availability

HIF2α is overexpressed in many tumours, including gastric cancer. HIF-2 significantly correlates with cancer clinical stages affecting proliferation, invasion and metastasis. It implements different functions during the tumour development process.

What are the Similarities Between HIF-1 and HIF-2?

HIF-1 and HIF-2 are heterodimeric transcription factors which are isoforms.
Both are composed of alpha and beta subunits.
Both activate HRE-dependent gene transcription.
They are regulators of oxygen homeostasis.
They mediate the cellular response to hypoxia.
Post-translational regulation of the α-subunit controls the stability and transactivation of HIF-1 and HIF-2.
The elevated expression of HIF-1 and HIF-2 is a key feature of many human cancers.
They promote cellular processes, which facilitating tumour progression.
Both HIF-1 and HIF-2 bind to the same hypoxia-response element DNA consensus sequence in target gene promoters.

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

HIF-1 is the main regulator of responses to hypoxia while HIF-2 is a major determinant factor of invasion and metastasis in various tumours. So, this is the key difference between HIF-1 and HIF-2. HIF-1 α and HIF-1 β are the two types of HIF-1 while HIF-2 α and HIF-2 β are the two types of HIF-2.

The below infographic tabulates the differences between HIF-1 and HIF-2 in more detail.

Summary – HIF-1 vs HIF-2

In hypoxia condition, our blood does not carry enough oxygen for tissues to fulfil their needs. It is a dangerous condition since the lack of oxygen to tissues and organs can create serious complications. HIF-1 and HIF-2 are regulators of oxygen homeostasis. They are transcription factors formed by α subunits and β subunits. They are isoforms. HIF-1 is the main regulator of responses to hypoxia while HIF-2 is a major determinant factor of invasion and metastasis in various tumours. Thus, this is the key difference between HIF-1 and HIF-2.

Reference:

1. “HIF1A.” Wikipedia, Wikimedia Foundation, 13 Sept. 2020, Available here.
2. Cerychova, Radka, and Gabriela Pavlinkova. “HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart.” Frontiers, 26 July 2018, Available here.

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