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HIF-2 alpha: HIF1A's Homologue with Similar and Divergent Functions

Thu, 04/14/2016 - 13:19

HIF-2 alpha is a member of the heterodimeric hypoxia-inducible factors/HIFs family (HIF-1, HIF-2, and HIF-3) which contains a common beta subunit but differ in their alpha subunits. Also called as EPAS1 or Mop2, HIF-2 alpha regulates cellular adaptation to hypoxia which is involved in several biological processes such as angiogenesis, cellular survival/proliferation, energy metabolism, erythropoiesis, extra-cellular matrix functions, invasion/ metastasis, iron metabolism, pH regulation, multidrug resistance, stem cell properties. The expression of HIF-2 alpha is regulated through hypoxia-dependent protein stabilization with the help of proteins PHDs (prolyl hydroxylase-domain enzymes) that initiate HIF2 degradation via the pVHL (von Hippel–Lindau protein). PHDs' activity is inhibited under hypoxic conditions which leads to the accumulation of HIF-2 alpha in cells followed by its nuclear translocation. Nuclear HIF2 alpha forms a dimeric complex with constitutively expressed HIF-1 beta / ARNT (aryl hydrocarbon receptor nuclear translocator) which then binds to HIF-1 alpha hypoxia response element/HRE leading to the activation of hypoxia responsive genes. HIF-2 alpha shares 48% amino-acid sequence homology with HIF-1 alpha and is now known to exert similar as well as divergent roles (especially in tumors) compared to HIF1 alpha. Studies have shown that HIF1 alpha is mostly active during 2-24 hours of hypoxic/anoxic trigger (<0.1% O2), whereas HIF2 alpha continue to be active even after 2-3 days of physiological hypoxia (<5% O2) suggesting that in certain contexts, HIF-1 participates in the initial stages of hypoxia, while HIF-2 drives the response to chronic hypoxia [1].

hif2a antibody

hif2a antibody

HIF-2 alpha/EPAS1 Antibody [NB100-122]
Western blot analysis of lysates from MDA-MB-231 cells which were subjected to normoxic/hypoxic conditions or transfection using empty, HIF1A or HIF2A overexpression vectors. This HIF-2 alpha antibody did not cross-react with HIF-1 alpha protein.

HIF-2 alpha Antibody (ep190b) [NB100-132]
IHC-P analysis of a formalin fixed and paraffin embedded tissue section of human endometrium using HIF-2 alpha/EPAS1 antibody (clone ep190b) at 1:250 dilution with overnight 4C incubation. The IHC assay involved an antigen retrieval step and blocking using 10% normal serum.

HIF2 alpha antibodies which are highly specific and do not react with its homologue HIF1 alpha are essential to immunoassays based analysis of HIF2 alpha's role in hypoxia signaling. Novus Biologicals offers high quality antibodies to various HIFs including HIF2 alpha with NB100-122 alone being cited in more than 400 publications on diverse experimental models.

In a recent publication from Nature Communications, Nakazawa et al. 2016 from University of Pennsylvania used Novus' HIF-2 alpha antibody [NB100-122] in Western blot and Chromatin immunoprecipitation/ChIP assays, and established that the human soft tissue sarcomas/STS have epigenetically silenced HIF-2 alpha and that the epigenetic re-expression of HIF-2 alpha suppresses soft tissue sarcoma growth [2]. In another study published in Plos One, Saini et al 2016 employed our HIF-2 alpha antibody [NB100-122] for Immunohistochemistry-Paraffin staining of tissues from lung specific HIF1 and/or HIF2 knockout mice and demonstrated a non-redundant function for HIF-1 alpha /HIF-2 alpha in lung development and identified hypoxia mediated signaling pathways which gets impacted upon HIFs manipulation [3]. Espana-Agusti et al 2016 used Novus' HIF-2 alpha/EPAS1 antibody (clone ep190b) [NB100-132] in Immunohistochemistry-Frozen analysis of kidneys from mice with combinations of Pax8-CreERT2, Slc22a6-CreERT2 and the Vhl floxed (fl) and wild-type (+) alleles. The authors found an increased expression of VHL's target protein HIF2 alpha and its downstream targets CAIX and GLUT1 proteins [4]. Dr Schokrpur from University of California Los Angeles used HIF-2 alpha/EPAS1 antibody (clone ep190b) [NB100-132] for Immunocytochemistry/Immunofluorescence staining analysis of RC control and RVN VHL cell lines which were generated using CRISPR-mediated knockout of VHL in the RENCA cell line (derived from murine spontaneous renal cortical adenocarcinoma). RVN cells (RENCA VHL knockout) depicted enhanced nuclear levels of HIF-1 as well as HIF-2 alpha but a reduced growth rate with increased migratory potential compared to RC control cells [5].

HIF-2 Alpha Products from Novus Biologicals:

Compiled by: Subhash Gangar


  • Koh MY, Powis G. 2012. Passing the baton: the HIF switch. Trends Biochem Sci.  37(9):364-72.
  • Nakazawa MS, Eisinger-Mathason TS, Sadri N et al. Epigenetic re-expression of HIF-2 [alpha] suppresses soft tissue sarcoma growth. Nat Commun. 2016 Feb 3; 7:10539.
  • Saini Y, Proper SP, Dornbos P et al. 2015. Loss of Hif-2 alpha rescues the Hif-1 alpha deletion phenotype of neonatal respiratory distress in mice. PLoS One. 10(9):e0139270
  • Espana-Agusti J, Zou X, Wong K et al. 2016. Generation and Characterisation of a Pax8-CreERT2 Transgenic Line and a Slc22a6-CreERT2 Knock In Line for Inducible and Specific Genetic Manipulation of Renal Tubular Epithelial Cells. PLoS One. 2016 Feb 11;11(2):e0148055
  • Schokrpur, S., 2015. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated development of an improved model for metastatic renal cell carcinoma. UCLA Thesis

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