FIH-1/HIF-1AN - a transcriptional regulator of HIF-1 alpha in oxygen sensing and beyond

Thu, 03/19/2015 - 15:36

FIH-1/HIF-1AN (factor inhibiting hypoxia-inducible factor-1/ HIF1AN) is a 40.3kDa protein which is expressed as asparaginyl hydroxylase enzyme in various multicellular organisms from worms/flies to mouse/rat and human beings. It functions as an oxygen sensor and, under normoxic conditions, FIH-1/HIF-1AN mediated hydroxylation prevents interaction of HIF-1 alpha with transcriptional coactivators including Cbp/p300-interacting transactivator, and it implicates in transcriptional repression process via interaction with HIF1A, VHL and HDACs. On the other hand, under hypoxic conditions, FIH-1/HIF-1AN is inactive, which leads to the activation of HIF-alpha signaling. FIH-1/HIF-1AN is mainly a cytoplasmic protein which functions inside the nuclei of cells and Liang et al 2015 have shown that the nuclear entry of FIH-1/HIF-1AN depends on HIF-1 alpha and copper (Cu), the latter being known to be critical for transcription activity of HIF1 alpha (1). Hydroxylation via Prolyl Hydroxylases/PHDs (EGLN2/PHD1, EGLN1/PHD2, EGLN3/PHD3 and PHD4/HIF Prolyl Hydroxylase 4) followed by proteosome degradation is another mechanism that regulates HIF1, however, FIH-1/HIF-1AN is able to exercise the control even under extremely hypoxic situations, when PHD enzymes fail to do so. Inside the nucleus, FIH-1/HIF-1AN hydroxylates an asparagine/Asn residue of HIF-1 alpha, whereas the other dioxygenases, PHDs, hydroxylate the proline residues of HIF-1 alpha in the cytosol of cells.

wb FIH-1/HIF1AN antibody Factor Inhibiting HIF-1 Antibody IHC>

WB analysis of a lysate from rat’s astrocytes using FIH-1/HIF-1AN antibody NB100-428 at 1:500 dilution with ECL detection. The antibody detected a major band at ~40 kDa position representing FIH-1/HIF-1AN protein.

IHC-P analysis of formalin fixed paraffin embedded section of human renal cancer tissue using FIH-1/HIF-1AN antibody (clone 162c) NBP1-30333 at 1:400 dilution with DAB with hematoxylin counterstain. The cancer cells depicted cytoplasmic immunopositivity for FIH-1/HIF-1AN protein.

FIH-1/HIF-1AN was originally identified as a protein that interacts with and biochemically inhibits the activity of HIF-1 alpha in C-terminal transactivation domain/CTAD by coupling the oxidative decarboxylation of 2-oxoglutarate to the hydroxylation of HIF-1 alpha at 'Asp-803' residue, however, subsequent research established that it also hydroxylates the specific Asn residues within ankyrin repeat domains/ARD of several ARD containing proteins such as NFkB-1, IkB-alpha/NFKBIA, Notch-1, ASB4, Myosin Phosphatase/PPP1R12A etc. Researchers have been continuously attempting to unfold the diverse roles of FIH-1/HIF-1AN in biological processes which are not limited to oxygen sensing signaling and this protein has been finding considerable attention in scientific community in recent past. So et al 2014 demonstrated that FIH-1/HIF-1AN functions as an essential anti-angiogenic factor in zebrafish vascular development via its physical interaction with Mind Bomb 1/MIB1 which is an E3 Ubiquitin ligase critically implicated in modulation of Notch-1 signaling during embryonic development (2). With a series of experiments involving human colorectal cancer/CRC tissues and in-vitro as well as in-vivo models, Chen et al 2015 demonstrated that FIH-1/HIF-1AN functions as a tumor suppressor protein in human CRC via repression of HIF1 alpha signaling/target genes (3). Peng et al 2014 found that FIH-1/HIF-1AN null mutant mice exhibit delayed wound healing and their mechanistic studies further established that FIH-1/HIF-1AN’s effects on cellular migration is independent of Notch and is in fact executed via its novel binding with leucine-rich repeat kinase 1/LRRK1 for the regulation of EGFR/MAPK signaling followed by ERK1/2 activation (4). Sharp’s team generated microRNA-deficient tumors by knocking out Dicer-1 gene and they found that these tumors are highly hypoxic with poor vascularization which was primarily mediated via depression of FIH-1/HIF-1AN in the tumor cells (5).

Novus Biologicals offers a variety of FIH-1/HIF-1AN products for your research needs including:


  1. PMID: 25687434
  2. PMID: 25347788
  3. PMID: 25602156
  4. PMID: 25455687
  5. PMID: 24788094

By: Subhash Gangar

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