10. Hypoxia Signalling 

 

The deficiency in the level of oxygen in tissue is hypoxia, which corresponds to both physiological and pathological disorders (Corrado C and Fontana S., 2020). 

 

Hypoxia leads to cellular reactions as a result of the induction of a number of genes, which play role in angiogenesis, glucose metabolism, cell survival and cell proliferation (Nakayama K and Kataoka N., 2019) (Corrado C and Fontana S., 2020).

 

Hypoxia Inducible Factor (HIF), which is a family of transcription factors, containing a heterodimer of HIF-α (oxygen related subunit) and HIF-β (constitutively expressed subunit), is the main factor that regulates cellular responses in aforementioned biological processes (Semenza G L., 2007 as cited in Corrado C and Fontana S., 2020) (Corrado C and Fontana S., 2020).

 

The feature that plays role in the stability and transcriptional activity of HIFs in hypoxia rests on prolyl-4-hydroxilases (PHDs) and factors inhibiting HIF-α (FIHs) respectively (Semenza G L., 2007) (Corrado C and Fontana S., 2020).

 

In normoxia, ubiquitination through E3 ubiquitin ligase Von Hippel- Lindau protein (pVHL) and ultimately the proteasome degradation is promoted as HIF-α proline residue (Pro564 on HIF1-α, Pro530 on HIF2-α and Pro490 on HIF3-α) is hydroxylated by PHD (Bruick R K and McKnight S L., 2001 as cited in Corrado C and Fontana S., 2020) (Maynard M A et al., 2003) (Jaakkola P M et al., 2001 as cited in Corrado C and Fontana S., 2020) (Corrado C and Fontana S., 2020).

 

In hypoxia, HIF-α hydroxylation is repressed which results in its nuclear translocation and its dimerisation with the HIF-β. According to Slemc L and Kunej T., 2016) (Corrado C and Fontana S., 2020 “This, in turn, facilitates attachment of this heterodimeric complex to hypoxia-responsive element (HERs), which is the DNA binding regions of its target genes, and this process ultimately results in control of their transcriptional activities” (Slemc L and Kunej T., 2016 as cited in Corrado C and Fontana S., 2020) (Corrado C and Fontana S., 2020). As a result of the occurrence of these procedures approximately 100 target genes are activated, among which are erythropoietin (EPO) and vascular endothelial growth factor (VEGF) (Lappin T R and Lee F S., 2019) (Jiang S et al., 2020 as cited in Corrado C and Fontana S., 2020) (Corrado C and Fontana S., 2020). These ultimately result in the induction of hypoxia related signalling pathways such as Nuclear Factor κB (NFκB) and Toll-like receptors (TLRs) in order to reinstate tissue homeostasis (Wu G et al., 2018) (Mak P et al., 2015) (Corrado C and Fontana S., 2020).

 

There are evidences of the regulatory role of PI3K/PKB (Protein Kinase B or AKT) and PKA (Protein kinase A) of HIF. Furthermore, repression of proteasomal degradation and stability of HIF1-α is regulated through its PKA phosphorylation and nuclear accretion of HIF1-α is advanced by MAPK/ERK pathway (Kietzmann T et al., 2016) (Xiao Y et al., 2017) (Zhang Z et al., 2018) (Mylonis I et al., 2017) (Corrado C and Fontana S., 2020).

 

Hypoxia Signalling References

 

1.        Bruick, R. K. & McKnight, S. L. A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF. Science (80-. ).294, 1337–1340 (2001).

2.        Corrado, C. & Fontana, S. Hypoxia and HIF Signaling: One Axis with Divergent Effects. Int. J. Mol. Sci. 21, 5611 (2020).

3.        Jaakkola, P. et al. Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation. Science (80-. ). 292, 468–472 (2001).

4.        Jiang, S. et al. P-21-activated kinase 1 contributes to tumor angiogenesis upon photodynamic therapy via the HIF-1α/VEGF pathway. Biochem. Biophys. Res. Commun. 526, 98–104 (2020).

5.        Kietzmann, T., Mennerich, D. & Dimova, E. Y. Hypoxia-Inducible Factors (HIFs) and Phosphorylation: Impact on Stability, Localization, and Transactivity. Front. Cell Dev. Biol. 4, (2016).

6.        Lappin, T. R. & Lee, F. S. Update on mutations in the HIF: EPO pathway and their role in erythrocytosis. Blood Rev. 37, 100590 (2019).

7.        Mak, P., Li, J., Samanta, S. & Mercurio, A. M. ERβ regulation of NF-κB activation in prostate cancer is mediated by HIF-1. Oncotarget 6, 40247–40254 (2015).

8.        Maynard, M. A. et al. Multiple Splice Variants of the Human HIF-3α Locus Are Targets of the von Hippel-Lindau E3 Ubiquitin Ligase Complex. J. Biol. Chem. 278, 11032–11040 (2003).

9.        Mylonis, I., Kourti, M., Samiotaki, M., Panayotou, G. & Simos, G. Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia. J. Cell Sci. (2016). doi:10.1242/jcs.195339

10.     Semenza, G. L. Hypoxia-Inducible Factor 1 (HIF-1) Pathway. Sci. STKE 2007, (2007).

11.     Slemc, L. & Kunej, T. Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature. Tumor Biol. 37, 14851–14861 (2016).

12.     Wu, G. et al. Hypoxia Exacerbates Inflammatory Acute Lung Injury via the Toll-Like Receptor 4 Signaling Pathway. Front. Immunol. 9, (2018).

13.     Xiao, Y. et al. PDGF Promotes the Warburg Effect in Pulmonary Arterial Smooth Muscle Cells via Activation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway. Cell. Physiol. Biochem. 42, 1603–1613 (2017).

14.     Zhang, Z., Yao, L., Yang, J., Wang, Z. & Du, G. PI3K/Akt and HIF‑1 signaling pathway in hypoxia‑ischemia (Review). Mol. Med. Rep. (2018). doi:10.3892/mmr.2018.9375