Table 2.
Genes and molecular mechanisms correlated with erythropoiesis in the HIF-EPO pathway.
| Gene Symbol | Gene ID | Protein Name | Category | Mechanism | Ref. |
|---|---|---|---|---|---|
| Regulation of HIF2α transcription | |||||
| E2F1 # | 1869 | Transcription factor E2F1 | 1 | Transcriptional activation of EPAS1 | [24] |
| OTUD7B # | 56957 | OTU domain-containing protein 7B (Cezanne) | 2 | Transcriptional activation of EPAS1 | [24] |
| ZC3H12A # | 80149 | MCP-induced protein 1 (MCPIP1) | 1 | Negative transcriptional regulation of EPAS1 | [25] |
| SP1 # | 6667 | Transcription factor Sp1 | 1 | Transcriptional activation of EPAS1 | [26] |
| SP3 # | 6670 | Transcription factor Sp3 | 1 | Transcriptional activation of EPAS1 | [26] |
| PI3K # | Phosphatidylinositol 3-kinase | 2 | Transcriptional activation of EPAS1 | [27] | |
| MTOR # | 2475 | Serine/threonine-protein kinase mTOR | 2 | Transcriptional activation of EPAS1 | [27] |
| DNMT1 # | 1786 | DNA (cytosine-5)-methyltransferase 1 (DNMT1) | 1 | Negative transcriptional regulation of EPAS1 | [29] |
| HIF2α protein modifications and protein interactions | |||||
| HIF1AN | 55662 | Hypoxia-inducible factor 1-alpha inhibitor (FIH-1) | 1 | Hydroxylation | [22] |
| CSNK2A1 | 1457 | Casein kinase II subunit alpha (CKIIα) | 1 | Phosphorylation | [30] |
| CSNK1D # | 1453 | Casein kinase I isoform delta (CKIδ) | 1 | Phosphorylation and nuclear transport | [32] |
| MAPK 1/3 # | 5594/5595 | Mitogen-activated protein kinase 1/3 (MAPK 1/3) | 1 | Phosphorylation and nuclear transport | [31] |
| SIRT1 # | 23411 | NAD-dependent protein deacetylase sirtuin-1 (hSIRT1) | 1 | Deacetylation | [33] |
| SENP1 # | 29843 | Sentrin-specific protease 1 | 1 | Desumoylation | [40] |
| RNF4 # | 6047 | E3 ubiquitin-protein ligase RNF4 | 1 | Ubiquitination | [40] |
| USP8 # | 9101 | Ubiquitin carboxyl-terminal hydrolase 8 (USP8) | 1 | Deubiquitination | [46] |
| USP29 | 57663 | Ubiquitin carboxyl-terminal hydrolase 29 (USP29) | 1 | Deubiquitination | [47] |
| IKBKG | 8517 | NF-kappa-B essential modulator (NEMO) | 1 | Other interaction proteins | [22] |
| KLHL20 # | 27252 | Kelch-like protein 20 (KLHL20) | 1 | Other interaction proteins | [48] |
| SART1 (HAF) | 9092 | Hypoxia-associated factor (HAF) | 1 | Other interaction proteins | [49] |
| BHLHE41 (SHARP1) | 79365 | Class E basic helix-loop-helix protein 41 (bHLHe41) | 4 | Other interaction proteins | [50] |
| EIF3E (INT6) | 3646 | Eukaryotic translation initiation factor 3 subunit E (eIF3e) | 1 | Other interaction proteins | [52] |
| PHD2 protein modifications and protein interactions | |||||
| FKBP8 | 23770 | Peptidyl-prolyl cis-trans isomerase FKBP8 (PPIase FKBP8) | 1 | Other interaction proteins | [53] |
| OS-9 | 10956 | Protein OS-9 (OS-9) | Other interaction proteins | [54] | |
| CBFA2T3 (MTG16) # | 863 | Protein CBFA2T3 (CBFA2T3) | 1 | Other interaction proteins | [55] |
| PTGES3 (P23) | 10728 | Prostaglandin E synthase 3 (PTGES3) | 1 | Other interaction proteins | [55] |
| LIMD1 | 8994 | LIM domain-containing protein 1 | 1, 4 | Other interaction proteins | [57,58] |
| VHL protein modifications and protein interactions | |||||
| LIMD1 | 8994 | LIM domain-containing protein 1 | 1, 4 | Other interaction proteins | [58] |
| DNMT3A | 1788 | DNA (cytosine-5)-methyltransferase 3A (DNMT3a) | 1 | MethylationNegative transcriptional regulation of VHL | [35] |
| DNMT3B | 1789 | DNA (cytosine-5)-methyltransferase 3B (DNMT3b) | 1 | MethylationNegative transcriptional regulation of VHL | [35] |
| UBE2S | 27338 | Ubiquitin-conjugating enzyme E2 S (E2-EPF) | 1, 4 | UbiquitinationDegradation of VHL | [45] |
| PIAS4 | 51588 | E3 SUMO-protein ligase PIAS4 (PIASY) | 1, 4 | Sumoylation | [39] |
| CDH1 | 999 | Cadherin 1 | 1 | UbiquitylationDegradation of VHL | [43] |
| WSB1 | 26118 | WD repeat and SOCS box-containing protein 1 (WSB1) | 1 | UbiquitinationDegradation of VHL | [44] |
| SMURF1 | 57154 | E3 ubiquitin-protein ligase SMURF1 (hSMURF1) | 1 | UbiquitinationDegradation of VHL | [42] |
| USP9X | 8239 | Probable ubiquitin carboxyl-terminal hydrolase FAF-X | 2, 4 | DeubiquitylationDegradation of VHL | [42] |
| ELOB | 6923 | Elongin-B (ELOB) | 2 | Other interaction proteinsUbiquitination of HIFα | [59] |
| ELOC | 6921 | Elongin-C (ELOC) | 1 | Other interaction proteinsUbiquitination of HIFα | [59] |
| CUL2 | 8453 | Cullin-2 (CUL-2) | 2 | Other interaction proteinsUbiquitination of HIFα | [59] |
| RBX1 | 9978 | E3 ubiquitin-protein ligase RBX1 | 2 | Other interaction proteinsUbiquitination of HIFα | [59] |
| SAT2 | 112483 | Thialysine N-epsilon-acetyltransferase (SSAT-2) | 1, 4 | Other interaction proteins | [60] |
| TCP1 | 6950 | T-complex protein 1 subunit alpha (TRiC) | 1 | Other interaction proteins | [61] |
| ID2 # | 3398 | DNA-binding protein inhibitor ID-2 (ID2) | 1 | Other interaction proteins | [62] |
| FIH protein modifications and protein interactions | |||||
| SIAH1 | 6477 | E3 ubiquitin-protein ligase SIAH1 | 2 | Ubiquitination | [22] |
| NFKBIA | 4792 | NF-kappa-B inhibitor alpha | 2 | Other interaction proteins | [22] |
| NFKB1 | 4790 | Nuclear factor NF-kappa-B p105 subunit | 2 | Other interaction proteins | [22] |
| NOTCH1/2/3 | 4851/4853/4854 | Neurogenic locus notch homolog protein 1/2/3 (Notch 1/2/3) | 2 | Other interaction proteins | [22] |
| ASB4 | 51666 | Ankyrin repeat and SOCS box protein 4 (ASB-4) | 2 | Other interaction proteins | [22] |
| CUX1 | 1523 | Homeobox protein cut-like 1 | 2 | DNA protein partner | [63] |
| PRKCZ | 5590 | Protein kinase C zeta type | 3 | Other interaction proteins | [63] |
| ARNT protein modifications and protein interactions | |||||
| UBE2I # | 7329 | SUMO-conjugating enzyme UBC9 | 2 | Sumoylation | [36] |
| PIAS1 # | 8554 | E3 SUMO-protein ligase PIAS1 | 2 | Sumoylation | [36] |
| AHR # | 196 | Aryl hydrocarbon receptor (AHR) | 2 | DNA protein partner | [64] |
| TACC3 | 10460 | Transforming acidic coiled-coil-containing protein 3 | 2 | DNA protein partnerCo-activator of HIF2 complex | [65] |
| Nuclear transport of key players of oxygen-sensing pathway | |||||
| KPNA2 # | 3838 | Importin subunit alpha-1 (Importinα) | 1 | Nuclear import of HIF2α, ARNT | [68] |
| KPNB1 # | 3837 | Importin subunit beta-1 (Importinβ) | 1 | Nuclear transport of HIF2α, ARNT | [68] |
| XPO1 | 7514 | Exportin-1 (CRM1) | 1 | Nuclear export of HIF2α, PHD2 | [31,66] |
| EEF1A1 | 1915 | Elongation factor 1-alpha 1 (eEF1A) | 1 | Nuclear export of VHL | [69] |
| Regulation of EPO transcription | |||||
| EP300 | 2033 | Histone acetyltransferase p300 (p300) | 1 | Transcriptional activation of EPO (co-activator) | [15,71] |
| CREBBP | 1387 | CREB-binding protein (CBP) | 1 | Transcriptional activation of EPO (co-activator) | [15] |
| HNF4A | 3172 | Hepatocyte nuclear factor-4α (HNF4α) | 1 | Transcriptional activation of EPO | [72] |
| RXRA | 6256 | Retinoid X receptor alpha (RXRα) | 1 | Transcriptional activation of EPO | [73] |
| NCOA3 (SRC3) # | 8202 | Nuclear receptor coactivator 3 (NCoA-3) | 1, 4 | DNA protein partner | [71] |
| RELA | 5970 | Transcription factor p65 (NFKB3) | 1, 4 | Transcriptional activation of EPO | [74,75] |
| GATA2 | 2624 | Endothelial transcription factor GATA-2 (GATA-2) | 1 | Negative transcriptional regulation of EPO | [77] |
| GATA3 | 2625 | Trans-acting T-cell-specific transcription factor GATA-3 (GATA-3) | 1 | Negative transcriptional regulation of EPO | [77] |
| MECP2 | 4204 | Methyl- CpG binding protein 2 (MeCP2) | 1 | Negative transcriptional regulation of EPO | [78] |
| p300 protein modifications and protein interactions | |||||
| SIRT1 | 23411 | NAD-dependent protein deacetylase sirtuin-1 (hSIRT1) | 2 | Deaceltylation | [34] |
| UBE2I | 7329 | SUMO-conjugating enzyme UBC9 | 2 | Sumoylation | [37] |
| SENP3 | 26168 | Sentrin-specific protease 3 | 2 | Desumoylation | [41] |
| CBP protein modifications and protein interactions | |||||
| UBE2I | 7329 | SUMO-conjugating enzyme UBC9 | 2 | Sumoylation | [38] |
# Experiments were performed in cancer cell lines, or cells other than renal cells, or it was a cancer-directed study. Category: 0—genes involved in erythropoiesis; 1—protein partners of 0; 2—protein partners of 1; 3—protein partners of 2; 4—protein partners of 0 or 1, but only proven with HIF1α or cancer study. Abbreviation list: CBFA2T3—core-binding factor, runt domain, alpha subunit 2; translocated to, 3; CREB—cAMP-responsive element-binding protein; CRM1—chromosomal region maintenance 1; E2F—E2 factor; EP300—E1A binding protein p300; FAF-X—Fat facets protein-related, X-linked; FIH—Factor Inhibiting HIF; FKBP8—FK506 binding protein 8; ID—inhibitor of DNA binding; IKBKG—inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; KPNA—karyopherin subunit alpha; KPNB—karyopherin subunit beta; MCP- monocyte chemotactic protein; MTG—myeloid translocation gene; mTOR—mechanistic target of rapamycin kinase; OS-9—Osteosarcoma Amplified 9; PIAS—protein inhibitor of activated STAT; RBX1—ring box 1; RNF—RING finger; SART1—spliceosome associated factor 1, recruiter of U4/U6.U5 tri-snRNP; SAT2/SSAT-2—spermidine/spermine N1-acetyltransferase family member 2; SHARP1—Enhancer-of-split and hairy-related protein 1; SIAH—Seven In Absentia Homolog; SMURF1—Smad ubiquitination regulatory factor 1; SOCS—suppressor of cytokine signalling; Sp—specificity protein; SRC3—Steroid receptor coactivator protein 3; SUMO—small ubiquitin-like modifier; TRiC—TCP1 ring complex; UBC9—ubiquitin carrier protein 9; UBE2I—ubiquitin conjugating enzyme E2 I; USP—ubiquitin specific peptidase; ZC3H12A—zinc finger CCCH-type containing 12A.