Alternative titles; symbols
HGNC Approved Gene Symbol: HIF1AN
Cytogenetic location: 10q24.31 Genomic coordinates (GRCh38): 10:100,535,943-100,559,998 (from NCBI)
Hypoxia-inducible factor-1 activates transcription of genes whose protein products either increase oxygen availability by promoting erythropoiesis (see EPO; 133170) and angiogenesis (see VEGF; 192240) or mediate adaptive responses to oxygen deprivation, such as increased glycolytic metabolism. HIF1A (603348), whose expression is regulated by cellular oxygen concentration, is part of a heterodimer with the constitutively expressed HIF1B (ARNT; 126110). The C-terminal half of HIF1A contains multiple regulatory domains that interact with specific proteins, such as VHL (608537).
Using a yeast 2-hybrid screen of a brain cDNA library with transactivating domain C (TAD-C) and the inhibitory domain of HIF1A as bait, Mahon et al. (2001) isolated a cDNA encoding HIF1AN, which they designated FIH1. EST database analysis suggested that HIF1AN is expressed in multiple cell types. The deduced 349-amino acid HIF1AN protein is homologous to rat Pass1 and to fly and worm sequences, indicating evolutionary conservation of this protein family.
By binding analyses of truncated HIF1AN peptides, Mahon et al. (2001) showed that the inhibitory domain rather than the transactivating domains of HIF1A interacts with HIF1AN, although the presence of TAD-C optimizes binding. Functional analysis indicated that HIAF1AN inhibits HIF1A transcriptional activity in hypoxic and nonhypoxic cells. Further binding analysis determined that the N terminus of HIF1AN interacts with the N terminus of VHL, and that both interact with HIF1A at distinct sites (VHL with TAD-N of HIF1A), allowing the formation of ternary complexes of the 3 proteins. VHL, but not HIF1AN, interacts with and recruits HDAC1 (601241), HDAC2 (605164), and HDAC3 (605166) to HIF1A, thus functioning as a HIF1A corepressor. Mahon et al. (2001) proposed that HIF1AN may instead interact, either directly or indirectly, with other functionally and structurally distinct histone deacetylases.
Using mass spectrometry and coimmunoprecipitation analysis, Hoff et al. (2013) found that the ciliary proteins ANKS6 (615370), NPHP3 (608002), INVS (243305), and NEK8 (609799) interacted in a complex. ANKS6 also interacted with HIF1AN (606615). Coimmunoprecipitation experiments showed that HIF1AN facilitated formation of a complex containing rat Anks6 and human NPHP3 and INVS. Association of rat Anks6 with human NEK8 required hydroxylation of Anks6. Hoff et al. (2013) concluded that oxygen-dependent hydroxylation of ANKS6 by HIF1AN regulates the composition of the ANKS6-containing ciliary complex.
By genomic sequence analysis, Mahon et al. (2001) determined that the HIF1AN gene contains 8 exons and spans 14 kb.
By genomic sequence analysis, Mahon et al. (2001) mapped the HIF1AN gene to chromosome 10q24, a region deleted in gliomas in which increased HIF1A-mediated transactivation of downstream genes, such as VEGF, occurs.
Hoff, S., Halbritter, J., Epting, D., Frank, V., Nguyen, T.-M. T., van Reeuwijk, J., Boehlke, C., Schell, C., Yasunaga, T., Helmstadter, M., Mergen, M., Filhol, E., and 29 others. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nature Genet. 45: 951-956, 2013. [PubMed: 23793029] [Full Text: https://doi.org/10.1038/ng.2681]
Mahon, P. C., Hirota, K., Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1-alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15: 2675-2686, 2001. [PubMed: 11641274] [Full Text: https://doi.org/10.1101/gad.924501]