Alternative titles; symbols
HGNC Approved Gene Symbol: HIF1A
Cytogenetic location: 14q23.2 Genomic coordinates (GRCh38): 14:61,695,513-61,748,258 (from NCBI)
Hypoxia-inducible factor-1 (HIF1) is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. HIF1 is a heterodimer composed of a 120-kD HIF1-alpha subunit complexed with a 91- to 94-kD HIF1-beta subunit (Wang et al., 1995).
Wang et al. (1995) identified cDNAs encoding HIF1-alpha and HIF1-beta. They determined that HIF1-beta is identical to ARNT (126110). The predicted 826-amino acid HIF1-alpha contains a bHLH (basic helix-loop-helix)-PAS domain at its N terminus (see 602550). Northern blot and Western blot analyses indicated that HIF1 mRNAs and proteins are induced in cells exposed to 1% oxygen and decay rapidly upon return of the cells to 20% oxygen. Hogenesch et al. (1997) identified HIF1-alpha as MOP1 (member of the PAS superfamily 1). Using Northern blot analysis, they determined that HIF1-alpha is expressed as a 3.6-kb mRNA, with the highest levels in kidney and heart.
Wenger et al. (1996) isolated cDNAs encoding mouse Hif1-alpha. The predicted mouse and human proteins are 90% identical. Iyer et al. (1998) noted that there are several mouse Hif1-alpha isoforms encoded by alternatively spliced mRNAs containing alternative translational initiation sites. Sequence analysis revealed that these alternative splicing and alternative translation initiation events were unlikely to occur in humans. The 5-prime flanking and 5-prime untranslated regions of the human and mouse HIF1-alpha genes are 70% identical.
By RT-PCR of human embryonic kidney cells, Gothie et al. (2000) identified 2 HIF1A variants. One transcript contains an additional 3 nucleotides (TAG) compared with the cDNA cloned by Wang et al. (1995). This change results in an 827-amino acid protein, designated HIF1A-827, that has 2 amino acid changes upstream of the bHLH domain. The other variant has the TAG insertion and also lacks exon 14, which produces a frameshift and introduces a stop codon. The deduced 736-amino acid truncated protein, designated HIF1A-736, lacks the C-terminal transactivation and inhibitory domains. RT-PCR detected variable expression of all 3 variants in several human cell lines and skin fibroblasts; the major variant did not have the additional TAG. Other mammalian cells and various mouse tissues only expressed variants with the additional TAG and exon 14.
HIF1 has a key role in cellular response to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis, and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Maxwell et al. (1999) demonstrated a critical role for the von Hippel-Lindau tumor suppressor gene product VHL (608537) in HIF1 regulation. In VHL-defective cells, HIF-alpha subunits were constitutively stabilized and HIF1 was activated. Reexpression of VHL restored oxygen-dependent instability. VHL and HIF-alpha subunits coimmunoprecipitated, and VHL was present in the hypoxic HIF1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF1 is dissociated from VHL. These findings indicated that the interaction between HIF1 and VHL is iron dependent and that it is necessary for the oxygen-dependent degradation of HIF-alpha subunits. Maxwell et al. (1999) suggested that constitutive HIF1 activation may underlie the angiogenic phenotype of VHL-associated tumors.
HIF1 activity is controlled by the oxygen-regulated expression of the HIF1A subunit. Under nonhypoxic conditions, the HIF1A protein is subject to ubiquitination and proteasomal degradation. Sutter et al. (2000) reported that missense mutations and/or deletions involving several different regions of the HIF1A gene result in constitutive expression and transcriptional activity in nonhypoxic cells. The authors demonstrated that hypoxia results in decreased ubiquitination of HIF1-alpha and that missense mutations increase HIF1-alpha expression under nonhypoxic conditions by blocking ubiquitination.
Bruick (2000) presented evidence that hypoxia-induced HIF1-alpha activates expression of the gene encoding NIP3 (603293), which in turn primes cells for apoptosis under conditions of persistent oxygen deprivation. This pathway may play a role in cell death resulting from cerebral and myocardial ischemia.
Semenza (2000) reviewed the role of hypoxia and HIF1 in oxygen homeostasis. For example, whereas overall protein synthesis is inhibited in response to hypoxia, VEGF (192240) mRNA levels increase because of increased transcriptional activation. This induction is mediated by HIF1 binding to a hypoxia response element located 1 kb 5-prime to the transcriptional start site of VEGF. Semenza (2000) listed 28 other direct HIF1 target genes involved in energy metabolism, iron homeostasis, angiogenesis, and cell proliferation and viability. In addition, the review focused on the involvement of HIF1 in human disease pathophysiology, including myocardial ischemia, cerebral ischemia, retinal ischemia, pulmonary hypertension, preeclampsia, intrauterine growth retardation, and cancer.
Gothie et al. (2000) found that both HIF1A-827 and HIF1A-736 were upregulated by hypoxia in transfected human embryonic kidney cells. Both recombinant proteins dimerized with ARNT, induced the VEGF promoter in a dose-dependent manner, and were activated by hypoxia. However, the HIF1A-736 isoform was 3-fold less active than HIF1A-827, consistent with the lack of the C-terminal transactivation domain in the shorter protein. HIF1A-736 also competed with endogenous and transfected full-length HIF1A, suggesting that HIF1A-736 may modulate gene expression upon hypoxia.
Adipocyte differentiation is inhibited by hypoxia. Yun et al. (2002) found that hypoxia inhibited Pparg2 (601487) transcription in mouse fibroblasts, and overexpression of Pparg2 or Cebpb (189965) stimulated adipogenesis under hypoxic conditions. Furthermore, Hif1a-deficient fibroblasts were refractory to hypoxia-mediated inhibition of adipogenesis. Yun et al. (2002) found that the Hif1a-regulated gene Dec1 (BHLHB2; 604256) repressed Pparg2 promoter activation and functioned as an effector of hypoxia-mediated inhibition of adipogenesis.
Inactivation of the tumor suppressor gene PTEN (601728) and overexpression of VEGF are 2 of the most common events observed in high-grade malignant gliomas (see 137800). Gomez-Manzano et al. (2003) showed that transfer of PTEN to glioma cells under normoxic conditions decreased the level of secreted VEGF protein by 42 to 70% at the transcriptional level. Assays suggested that PTEN acts on VEGF most likely via downregulation of HIF1 and by inhibition of PI3K (601232).
In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the VHL tumor suppressor protein. Ivan et al. (2001) found that human VHL protein binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and iron, this protein modification may play a key role in mammalian oxygen sensing. Jaakkola et al. (2001) also demonstrated that the interaction between VHL protein and a specific domain of the HIF1-alpha subunit is regulated through hydroxylation of a proline residue (HIF1-alpha P564) by an enzyme which they termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as a cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.
Epstein et al. (2001) defined a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and identified Egl9 as a dioxygenase that regulates HIF by prolyl hydroxylation. In mammalian cells, they showed that the HIF-prolyl hydroxylases are represented by 3 proteins, PHD1 (606424), PHD2 (EGLN1; 606425), and PHD3 (606426), with a conserved 2-histidine-1-carboxylate iron coordination motif at the catalytic site. Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrored the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.
Prolyl hydroxylation of HIF1A by PHDs is prerequisite for HIF1A degradation. Nakayama et al. (2004) demonstrated that PHD1 and PHD3 abundance is regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases SIAH1 (602212) and SIAH2 (602213) under hypoxia conditions. Siah2-null mouse fibroblasts exhibited prolonged Phd3 half-life, resulting in lower levels of Hif1a expression during hypoxia. Hypoxia-induced Hif1a expression was completely inhibited in Siah1a/Siah2-null cells, yet could be rescued upon inhibition of Phd3 by RNA interference. In 293T cells, SIAH2 targeting of PHD3 for degradation increased upon exposure to even mild hypoxic conditions, which coincided with increased SIAH2 transcription. Siah2-null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. Nakayama et al. (2004) concluded that control of PHD1 and PHD3 by SIAH1 and SIAH2 constitutes another level of complexity in the regulation of HIF1A during hypoxia.
Baek et al. (2005) found that OS9 (609677) interacted with both HIF1A and PHDs in human 293 cells. Formation of this ternary complex promoted PHD-mediated hydroxylation of HIF1A, binding of HIF1A to VHL, and proteasomal degradation of HIF1A. Knockdown of OS9 by RNA interference increased HIF1A protein levels, HIF1A transcriptional activity, and VEGF mRNA levels under nonhypoxic conditions. Baek et al. (2005) concluded that OS9 is an essential component of a multiprotein complex that regulates HIF1A levels in an oxygen-dependent manner.
Ozer et al. (2005) found that ING4 (608524) suppressed expression of HIF target genes under hypoxic conditions. ING4 directly interacted with HPH2 (EGLN1), a mediator of HIF stability, providing a mechanism for ING4 recruitment to HIF. ING4 association with HPH2 did not affect hydroxylase activity or HIF stability, but it suppressed HIF activity in a chromatin-dependent manner. Ozer et al. (2005) hypothesized that ING4, recruited to HIF by HPH2 under hypoxic conditions, acts as an adaptor protein to recruit transcriptional repressors to mediate HIF activity.
Using cell lines stably expressing the C-terminal 100 amino acids of HIF2A (603349), which include the C-terminal transactivation domain (CTAD), and MALDI-TOF mass spectrometry analysis, Lando et al. (2002) determined that asn851 (equivalent to asn803 in HIF1A) is hydroxylated under normoxic but not hypoxic conditions, suggesting that an asparaginyl hydroxylase mediates silencing of HIF1A and HIF2A CTADs. Mutational analysis showed that replacement of asn with ala in these positions resulted in full transcriptional activity in normoxia. In contrast, replacement of pro853 in HIF2A or pro805 in HIF1A with ala resulted in loss of this activity in both normoxic and hypoxic conditions. Western blot analysis showed that asn hydroxylation silences the CTAD of HIF1A and HIF2A by preventing their interaction with the CH1 domain of p300 (602700)/CBP (600140). Lando et al. (2002) concluded that the hypoxic induction of HIF proteins involves (1) inhibition of oxygen-dependent hydroxylation on pro residues in the oxygen-dependent degradation domain to prevent interaction with the VHL ubiquitin ligase complex and proteasomal destruction, and (2) inhibition of the oxygen-dependent hydroxylation of asn in the CTAD regions to promote interaction with the p300/CBP coactivator and induce transcription. They proposed that the prolyl and asparaginyl hydroxylases are attractive targets for therapeutic regulation of HIF1A and HIF2A.
Expression of the mouse Hif1a gene is driven by 2 different promoters located 5-prime to 2 alternative first exons designated I.1 and I.2 (Wenger et al., 1997). The exon I.1-derived mRNA isoform is tissue-specific, whereas the exon I.2-derived isoform is ubiquitously expressed (Wenger et al., 1998). By in situ hybridization, Marti et al. (2002) detected Hif1a-I.1 mRNA exclusively in the elongated spermatids of the testis. In vitro studies indicated that the switch from Hif1a-I.2 to Hif1a-I.1 mRNA expression does not occur at the premeiotic stages of mouse spermatogenesis. Exposure of mice to hypoxic conditions induced Hif1a-I.2 protein in spermatocytes and probably in Sertoli cells but not in spermatogonia. The authors concluded that both the switch in transcript expression during spermiogenesis and the unexpected protein localization in mature sperm cells suggest a function of Hif1a.
Using the yeast 2-hybrid system to identify proteins that interact with the ODD domain of HIF1A, Jeong et al. (2002) identified ARD1 (300013). They established the function of ARD1 as a protein acetyltransferase in mammalian cells by direct binding to HIF1A to regulate its stability. Jeong et al. (2002) also showed that ARD1-mediated acetylation enhances interaction of HIF1A with VHL and HIF1A ubiquitination, suggesting that the acetylation of HIF1A by ARD1 is critical to proteasomal degradation. They concluded that the role of ARD1 in the acetylation of HIF1A provides a key regulatory mechanism underlying HIF1A stability.
Staller et al. (2003) demonstrated that the von Hippel-Lindau tumor suppressor protein (VHL; see 608537) negatively regulates CXCR4 (162643) expression owing to its capacity to target HIF1A for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutations in the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumor-specific survival. Staller et al. (2003) concluded that their results suggest a mechanism for CXCR4 activation during tumor cell evolution and imply that VHL inactivation acquired by incipient tumor cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.
Koshiji et al. (2005) demonstrated that HIF1A is responsible for the genetic instability characteristic of cells undergoing hypoxic stress. They determined that HIF1A acts as a transcriptional repressor of the MSH2 (609309) and MSH6 (600678) genes, thereby inhibiting mismatch recognition and DNA repair.
Gustafsson et al. (2005) found that hypoxia blocked differentiation of mammalian neuronal and myogenic progenitor cells in culture through a Notch (190198) signaling pathway. Hypoxia led to recruitment of Hif1a to Notch-responsive promoters and elevated expression of Notch downstream genes.
Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase (FH; 136850) and succinate dehydrogenases (see, e.g., SDHB, 185470) act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer (HLRCC; 150800) and to paragangliomas (see 115310), respectively. Pollard et al. (2005) showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A, activation of HIF1A targets like VEGF (192240), and high microvessel density. Pollard et al. (2005) hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paragangliomas and leiomyomas and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (193300).
VHL encodes an E3 ligase that promotes the ubiquitination of the alpha subunits of the hypoxia-inducible transcription factors HIF1, HIF2, and HIF3 (see 609976), leading to their degradation by the proteasome. Consequently, renal carcinomas with mutations in VHL have high steady-state levels of HIF expression. Functional studies show that HIF is sufficient for transformation caused by loss of VHL, thereby establishing HIF as the primary oncogenic driver in kidney cancers. Thomas et al. (2006) showed that loss of VHL sensitizes cancer cells to the rapamycin (mTOR) inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlated with a block in translation of mRNA encoding HIF1A, and was rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5-prime untranslated region. VHL-deficient tumors showed increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. The findings provided preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggested that FDG-PET scans may have use as a pharmacodynamic marker in this setting.
Bernardi et al. (2006) identified PML (102578) as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischemic and neoplastic conditions, through the control of protein translation.
Bernardi et al. (2006) demonstrated that in hypoxic conditions PML (102578) acts as a negative regulator of the synthesis rate of HIF1A by repressing MTOR (601231). These and other findings identified PML as a novel suppressor of MTOR and neoangiogenesis.
Sano et al. (2007) showed that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that accumulation of p53 (191170) is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by Hif1-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. Sano et al. (2007) concluded that the antiangiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.
Liu et al. (2007) showed that RACK1 (GNB2L1; 176981) interacted with HIF1A and promoted its proteasomal degradation through an oxygen-independent pathway. RACK1 competed with the HIF1A-stabilizing protein HSP90 (HSPCA; 140571) for HIF1A binding in vitro and in human cells, and RACK1 linked HIF1A to elongin C (ELOC; 600788), promoting ubiquitination of HIF1A. Liu et al. (2007) concluded that RACK1 is an essential component of an oxygen-independent mechanism for regulating HIF1A stability.
Wang et al. (2007) showed that mice overexpressing Hif1a in osteoblasts through selective deletion of Vhl expressed high levels of Vegf (192240) and developed extremely dense, heavily vascularized long bones. In contrast, mice lacking Hif1a in osteoblasts had long bones that were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Wang et al. (2007) concluded that activation of the HIF1A pathway in osteoblasts during bone development couples angiogenesis to osteogenesis.
Sikder and Kodadek (2007) found that orexin-1 (602358) stimulation of human embryonic kidney cells expressing orexin-1 receptor (OX1R, or HCRTR1; 602392) resulted in significant upregulation of a host of genes, including HIF1A. Orexin-1 stimulation also caused a concomitant downregulation of VHL. Chromatin immunoprecipitation assays revealed increased HIF1A occupancy on promoters of HIF1A target genes following orexin stimulation. The spectrum of HIF1A-induced genes differed in normoxic cells stimulated with orexin from those induced by hypoxia. Orexin-mediated activation of HIF1A resulted in increased glucose uptake and higher glycolytic activity, similar to what was observed in hypoxic cells. However, OX1R-expressing cells favored ATP production through the tricarboxylic acid cycle and oxidative phosphorylation rather than through anaerobic glycolysis. Sikder and Kodadek (2007) concluded that HIF1A, in addition to responding to hypoxia, has a role in hormone-mediated regulation of hunger and wakefulness.
Higgins et al. (2007) inactivated Hif1a in mouse primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO). They found that Hif1a enhanced epithelial-to-mesenchymal transition in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes (e.g., LOX; 153455). Ablation of epithelial Hif1a inhibited development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and reduced number of fibroblast-specific protein-1 (FSP1, or S100A4; 114210)-expressing interstitial cells. Higgins et al. (2007) also found that increased renal HIF1A expression was associated with tubulointerstitial injury in patients with chronic kidney disease.
See also a review by Semenza (2007).
Carbia-Nagashima et al. (2007) found that human RSUME (RWDD3; 615875) enhanced sumoylation of HIF1A in vitro and stabilized endogenous HIF1A in COS-7 cells during hypoxia.
Using mouse lacking Ikkb (IKBKB; 603258) in different cell types, Rius et al. (2008) showed that NF-kappa-B (164011) was a critical transcriptional activator of Hif1a and that basal NF-kappa-B activity was required for Hif1a protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. Ikkb deficiency resulted in defective induction of Hif1a target genes including Vegf. Ikkb was essential for Hif1a accumulation in macrophages experiencing a bacterial infection.
Using mouse models of diabetes and ischemia, Ceradini et al. (2008) showed that hyperglycemia interfered with Hif1a function and caused defective signaling in fibroblasts and bone marrow-derived endothelial progenitor cells in response to hypoxia. Increased superoxide levels resulting from hyperglycemia induced methylglyoxal modification of 2 arginines in the bHLH domain of Hif1a. This modification reduced Hif1a heterodimer formation and caused defective Hif1a binding to hypoxia-induced promoters, including those of Sdf1 (CXCL12; 600835), Cxcr4, eNos (NOS3; 163729), and Vegf. The effects of hyperglycemia, including modification of Hif1a, were prevented by overexpression of the methylglyoxyl-metabolizing enzyme, GLO1 (138750). Ceradini et al. (2008) concluded that defective HIF1A signaling causes the impaired ischemia-induced vasculogenesis observed in patients with diabetes.
Xenaki et al. (2008) found that PCAF (602303) functioned as a cofactor for HIF1A in human osteosarcoma cell lines treated with desferrioxamine (DSFX), a hypoxia-mimicking compound. PCAF and HIF1A interacted in DSFX-treated cells, resulting in PCAF-dependent acetylation of HIF1A. PCAF was recruited to the hypoxia response element of a subset of HIF1A targets, including the proapoptotic gene BID (601997) and the angiogenic gene VEGF. DSFX-treated cells also showed HIF1A-dependent apoptosis.
Mehta et al. (2009) reported that in C. elegans the loss of VHL1 (608537) significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF1 was epistatic to VHL1, indicating that HIF1 acts downstream of VHL1 to modulate aging and proteotoxicity. VHL1 and HIF1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. Mehta et al. (2009) concluded that their findings define VHL1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.
Zhao et al. (2009) showed that isocitrate dehydrogenase-1 (IDH1; 147700) carrying an arginine at codon 132 has reduced affinity for its substrate and dominantly inhibits wildtype IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduced formation of the enzyme product, alpha ketoglutarate (alpha-KG), and increased levels of HIF1-alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF1-alpha levels was reversible by an alpha-KG derivative. HIF1-alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, Zhao et al. (2009) concluded that IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF1 pathway.
Raspaglio et al. (2008) found that HIF1A induced TUBB3 (602661) expression in several human cell lines exposed to hypoxic stress. Chromatin immunoprecipitation analysis showed that HIF1A bound an HIF1A-binding site in the 5-prime flanking region of the TUBB3 gene.
Sendoel et al. (2010) showed that C. elegans HIF1, homologous to HIF-alpha, protects against DNA damage-induced germ cell apoptosis by antagonizing the function of CEP1, the homolog of p53 (191170). The antiapoptotic property of HIF1 is mediated by means of transcriptional upregulation of the tyrosinase family member TYR2 in the ASJ sensory neurons. TYR2 is secreted by ASJ sensory neurons to antagonize CEP1-dependent germline apoptosis. Knockdown of the TYR2 homolog TRP2 (also called DCT; 191275) in human melanoma cells similarly increased apoptosis, indicating an evolutionarily conserved function. Sendoel et al. (2010) concluded that their findings identified a novel link between hypoxia and programmed cell death, and provided a paradigm for HIF1 dictating apoptotic cell fate at a distance.
Porcelli et al. (2010) reported a high frequency of homoplasmic disruptive mitochondrial mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicated disassembly of respiratory complex I in vivo, which in turn may contribute to the inability of oncocytic tumors to stabilize HIF1 and to display pseudohypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), the authors induced a shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 (516000) gene. The shift was associated with a profound metabolic impairment leading to the imbalance of alpha-ketoglutarate and succinate, Krebs cycle metabolites which stabilize HIF1. The authors concluded that the main hallmarks of oncocytic transformation, namely, the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1 stabilization.
Baranello et al. (2010) showed that the anticancer agent camptothecin, which inhibits DNA topoisomerase I (TOP1; 126420), reduced expression of the primary HIF1A transcript and increased expression of the antisense transcripts 5-prime AHIF1A (HIF1AAS1; 614528) and 3-prime AHIF1A (614529) and in human cell lines.
The muscle pyruvate kinase isoforms PKM1 and PKM2 are both encoded by the PKM2 gene (179050). Using knockdown and overexpression studies with several human cell lines, Luo et al. (2011) showed that PKM2, but not PKM1, interacted with HIF1A and stimulated HIF1A transactivation activity under hypoxic conditions. Mutation analysis showed that PKM2 interacted with HIF1A at multiple sites. PKM2, but not PKM1, contains a prolyl hydroxylation motif, LxxLAP, that was hydroxylated by PHD3, and this hydroxylation was required for PKM2-mediated HIF1A activation. Chromatin immunoprecipitation analysis demonstrated colocalization of PKM2, PHD3, and HIF1A with p300 at hypoxia response elements under hypoxic conditions. PKM2, PHD3, and HIF1A were all required to induce transcription of glycolytic genes and the glucose transporter-1 gene (GLUT1, or SLC2A1; 138140). HIF1A also induced PKM2 expression in a positive-feedback loop during the shift from oxidative to glycolytic metabolism.
Using predominantly wildtype and Hif1a -/- mouse T cells, Dang et al. (2011) showed that Hif1a was specifically required for differentiation of naive T cells into interleukin 17 (IL17; 603149)-expressing helper T (Th) cells. Hif1a interacted directly with Ror-gamma-t (RORC; 602943) and p300 at the Il17 promoter, and all 3 factors were required for optimum Il17 expression. Simultaneously, Hif1a downregulated differentiation of naive T cells into regulatory T (Treg) cells by directing proteasomal degradation of the Treg-dependent transcription factor Foxp3 (300292) by a mechanism that was independent of Hif1a transcriptional activity. Differentiation of Th17 cells and loss of Treg cells was enhanced in cultures subjected to hypoxic conditions. Knockout of Hif1a in mouse T cells rendered mice highly resistant to Mog (159465)-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (see 126200). Dang et al. (2011) concluded that HIF1A has a role in immune responses by controlling the balance between Th17 and Treg cells.
Tannahill et al. (2013) showed that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1-beta (IL1B; 147720) but not tumor-necrosis factor-alpha (TNFA; 191160) in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages showed upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increased the levels of the tricarboxylic acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'gamma-aminobutyric acid (GABA) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes HIF1A, an effect that is inhibited by 2-deoxyglucose, with IL1B as an important target. Lipopolysaccharide also increased succinylation of several proteins. Tannahill et al. (2013) concluded that they had identified succinate as a metabolite in innate immune signaling that enhances IL1B production during inflammation.
Triple-negative breast cancer (see 114480), a form of breast cancer in which tumor cells do not express the genes for estrogen receptor (see 133430), progesterone receptor (PGR; 607311), and HER2 (ERBB2; 164870), is a highly aggressive malignancy with limited treatment options. Chen et al. (2014) reported that XBP1 (194355) is activated in triple-negative breast cancer and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumor growth and tumor relapse and reduced the CD44 (107269)-high/CD24 (600074)-low population. HIF1A is known to be hyperactivated in triple-negative breast cancers. Genomewide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives triple-negative breast cancer tumorigenicity by assembling a transcriptional complex with HIF1A that regulates the expression of HIF1A targets via the recruitment of RNA polymerase II (see 180660). Analysis of independent cohorts of patients with triple-negative breast cancer revealed a specific XBP1 gene expression signature that was highly correlated with HIF1A and hypoxia-driven signatures and that strongly associated with poor prognosis. Chen et al. (2014) concluded that their findings revealed a key function for the XBP1 branch of the unfolded protein response in triple-negative breast cancer.
Colegio et al. (2014) showed that lactic acid produced by tumor cells, as a byproduct of aerobic or anaerobic glycolysis, has a critical function in signaling, through inducing the expression of vascular endothelial growth factor (VEGF; 192240) and the M2-like polarization of tumor-associated macrophages. The authors also demonstrated that this effect of lactic acid is mediated by HIF1A. Finally, they showed that the lactate-induced expression of arginase-1 (ARG1; 608313) by macrophages has an important role in tumor growth. Colegio et al. (2014) concluded that their findings identified a mechanism of communication between macrophages and their client cells, including tumor cells. This communication likely evolved to promote homeostasis in normal tissues but can also be engaged in tumors to promote their growth.
Under hypoxic conditions, HIF1-alpha binds to the TAZ1 domain of the general transcriptional coactivators CBP (600140) and p300 (602700) to promote rapid activation of adaptive genes, including CITED2 (602937). CITED2 is a negative feedback regulator that attenuates HIF1 transcriptional activity by competing for binding to TAZ1. Both HIF1-alpha and CITED2 bind to TAZ1 through their respective disordered transactivation domains. The HIF1-alpha and CITED2 transactivation domains bind to TAZ1 through helical motifs that flank a conserved LP(Q/E)L sequence that is essential for negative feedback regulation. Berlow et al. (2017) demonstrated that human CITED2 displaces HIF1-alpha by forming a transient ternary complex with TAZ1 and HIF1-alpha and competing for a shared binding site through its LPEL motif, thus promoting a conformational change in TAZ1 that increases the rate of HIF1-alpha dissociation. Through allosteric enhancement of HIF1-alpha release, CITED2 activates a highly responsive negative feedback circuit that rapidly and efficiently attenuates the hypoxic response, even at modest CITED2 concentrations. This hypersensitive regulatory switch is entirely dependent on the unique flexibility and binding properties of these intrinsically disordered proteins and probably exemplifies a common strategy used by the cell to respond rapidly to environmental signals.
Liu et al. (2018) found that ILKAP (618909) bound directly to phosphorylated HIF1-alpha and dephosphorylated it in the tumor cell line A172. Subsequently, dephosphorylated HIF1-alpha separated from ILKAP and bound directly with p53, inducing apoptosis under both hypoxia and normoxia.
Stegen et al. (2019) demonstrated that prolonged HIF1-alpha signaling in chondrocytes leads to skeletal dysplasia by interfering with cellular bioenergetics and biosynthesis. Decreased glucose oxidation results in an energy deficit, which limits proliferation, activates the unfolded protein response, and reduces collagen synthesis. However, enhanced glutamine flux increases alpha-ketoglutarate levels, which in turn increases proline and lysine hydroxylation on collagen. This metabolically regulated collagen modification renders the cartilaginous matrix more resistant to protease-mediated degradation and thereby increases bone mass. Thus, Stegen et al. (2019) concluded that inappropriate HIF1-alpha signaling results in skeletal dysplasia caused by collagen overmodification, an effect that may also contribute to other diseases involving the extracellular matrix such as cancer and fibrosis.
Crystal Structure
The ubiquitination of HIF by the VHL tumor suppressor plays a central role in the cellular response to changes in oxygen availability. VHL protein binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. Min et al. (2002) determined the 1.85-angstrom structure of a 20-residue HIF1A-VHL protein-elongin B (600787)-elongin C complex that shows that HIF1A binds to VHL protein in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the VHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.
Hon et al. (2002) determined the crystal structure of a hydroxylated HIF1A peptide bound to the VHL protein, elongin C, and elongin B and performed solution binding assays, which revealed a single, conserved hydroxyproline-binding pocket in the VHL protein. They found that optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. Hon et al. (2002) concluded that this mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.
Wu et al. (2015) described the crystal structure for each of mouse Hif2-alpha (603349)-Arnt (126110) and Hif1-alpha-Arnt heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by Hif2-alpha-Arnt and Hif1-alpha-Arnt, wherein Arnt spirals around the outside of each Hif-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends, and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.
Iyer et al. (1998) reported that the HIF1-alpha gene contains 15 exons. The introns in HIF1-alpha and mouse Hif1-alpha are located in the same positions.
HIF1A Antisense Transcripts
Thrash-Bingham and Tartof (1999) identified an antisense transcript, HIF1AAS2 (614529), that overlaps the 3-prime UTR of the HIF1A gene in the opposite orientation. Baranello et al. (2010) identified an antisense transcript, HIF1AAS1 (614528), that overlaps exon 1 and intron 1 of the HIF1A gene in the opposite orientation.
By analysis of an interspecific backcross, Wenger et al. (1996) and Semenza et al. (1996) mapped the Hif1-alpha gene to mouse chromosome 12, in a region sharing homology of synteny with human chromosome 14q12-q32.33. By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Semenza et al. (1996) mapped the HIF1-alpha gene to 14q21-q24.
Yu et al. (1999) analyzed the physiologic responses of Hif1a +/- and wildtype mice exposed to 10% oxygen for 1 to 6 weeks and found that heterozygotes demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wildtype littermates. Yu et al. (1999) concluded that partial HIF1A deficiency has significant effects on multiple systemic responses to chronic hypoxia.
Elson et al. (2001) created transgenic mice overexpressing Hif1a in basal keratinocytes of skin and squamous epithelium. Transgenic mice displayed a 66% increase in dermal capillaries, a 13-fold elevation of total Vegf expression, and a 6- to 9-fold induction of each Vegf isoform. However, they did not show edema, inflammation, or vascular leakage, characteristics of transgenic mice overexpressing Vegf cDNA in skin.
To investigate whether HIF1 is required for ventilatory responses to hypoxia, Kline et al. (2002) analyzed mice that were either wildtype or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus. Although ventilatory response to acute hypoxia was not impaired in heterozygous Hif1a mice, the response was primarily mediated via vagal afferents, whereas in wildtype mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wildtype mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded. In contrast, carotid bodies from heterozygous mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in heterozygous mice. Wildtype mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in heterozygous Hif1a mice. Thus, partial HIF1A deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.
Cramer et al. (2003) examined the inflammatory response in mice with conditional knockouts of Hif1a, its negative regulator Vhl (608537), and a downstream target, Vegf. They found that activation of Hif1a was essential for myeloid cell infiltration and activation in vivo through a mechanism independent of Vegf. Loss of Vhl led to a large increase in acute inflammatory responses. When Hif1a was absent, the cellular ATP pool was drastically reduced, showing that HIF1A is essential for the regulation of glycolytic capacity in myeloid cells. The metabolic defect resulted in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. The authors concluded that this role for HIF1A demonstrates its direct regulation of survival and function in the inflammatory microenvironment.
In transgenic mice with targeted deletion of Hif1a in skeletal muscle, Mason et al. (2004) found that exercise induced a decrease in glycolytic enzyme activity and an increase in citric acid cycle enzymes and oxidation. Repeated exercise caused extensive muscle damage in the transgenic mice, similar to changes seen in humans with diseases caused by defects in glycogenolysis and glycolysis.
Tomita et al. (2003) created mice with neural-cell specific Hif1a deficiency. Mutant mice appeared normal at birth, and they showed no abnormality in body weight or mortality. However, they exhibited hydrocephalus accompanied by a reduction in neural cells and an impairment of spatial memory. Apoptosis of neural cells coincided with vascular regression in the telencephalon of mutant embryos. These defects were successfully restored by in vitro gene delivery of Hif1a to the embryos. Tomita et al. (2003) concluded that HIF1A in neural cells is essential for normal brain development.
Using neutrophils and bone marrow macrophages derived from Hif1a-lysMcre mice, which have specific deletion of Hif1a in cells of the myeloid lineage, Peyssonnaux et al. (2005) showed that Hif1a is induced by bacterial infection even under normoxia and regulates the production of key immune effector molecules, including granule proteases (e.g., neutrophil elastase, ELA2 130130; cathepsin G, CTSG 116830; and Cramp, the mouse homolog of cathelicidin, CAMP 600474), nitric oxide (see NOS2A, 163730), and Tnf 191160 through a nitric oxide-dependent process. Neutrophils and macrophages from Vhl-deficient mice, which have upregulated Hif1a expression, had increased expression of all of these mediators. Wildtype cells had intermediate expression of all of these molecules after bacterial infection unless the Hif1a pathway is induced by pharmacologic mediators. In vivo, the Hif1a-deficient mice developed significantly larger necrotic skin lesions, greater weight loss, and higher bacterial numbers after subcutaneous inoculation with group A Streptococcus. Peyssonnaux et al. (2005) suggested that HIF1A control of myeloid activity in infected tissues could represent a novel therapeutic target for enhancing host defense.
By examining T cells from mice lacking Vhl or both Vhl and Hif1a, Neumann et al. (2005) showed that Hif1a negatively regulated Ca(2+) signaling downstream of TCR ligation in a Serca2 (ATP2A2; 108740)-dependent manner.
Using genetic and pharmacologic approaches, Wan et al. (2008) showed that the Hif1 pathway was required to mediate the angiogenic and osteogenic phases of bone repair in the mouse distraction osteogenesis model of skeletal repair.
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