Disease relevance of HIF1A

• HIF is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau tumor suppressor protein (VHL) leads to rapid degradation of the HIF1A subunit [1].
• Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer [2].
• We also show that in hypoxia another sequence located upstream from the +1 initiation site plays an inhibitory role on HIF1A transcription in HMEC-1 but not in hepatoma cells and brings back this expression level to that observed in normoxia [3].
• Polymorphisms in the hypoxia inducible factor-1alpha gene (HIF1A) are associated with the renal cell carcinoma phenotype [4].
• In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density [5].
• During the late phase of intracellular chlamydial replication, host cell adaptation to hypoxia was actively silenced by pathogen-induced HIF-1alpha degradation [6].

Psychiatry related information on HIF1A

• In conclusion, these data clearly demonstrate that physical activity induces the HIF-1-mediated signaling pathway in human skeletal muscle, providing the first evidence that human HIF-1alpha can be activated during physiologically relevant conditions [7].
• Therefore, the use of immunohistochemical assessment of HIF-1alpha as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma [8].
• Therefore, HIF-1alpha expression in early stage oral carcinomas was evaluated in relation to established clinico-pathological features in order to determine its value as a prognostic marker [9].
• RESULTS: When the period of alcohol consumption increased, the positive rate of expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) mRNA was more significantly elevated in the liver of the alcohol group than in the control group (P</=0.05) [10].

High impact information on HIF1A

• The protein pVHL functions in a multi-subunit E3 ubiquitin ligase that targets the hypoxia-inducible transcription factor Hif1 alpha for proteasomal degradation during normoxia [11].
• Blockade of TBP-1 expression by small interfering RNA (siRNA) causes prolonged degradation kinetics of Hif1 alpha [11].
• Recently, prolyl hydroxylation was identified as a key regulatory event that targets the HIF-1alpha subunit for proteasomal degradation via the pVHL ubiquitination complex [12].
• Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation [12].
• A molecular basis for O(2)-regulated expression of the HIF-1 alpha subunit has now been determined, providing a mechanism for changes in gene expression in response to changes in cellular oxygenation [13].

Chemical compound and disease context of HIF1A

• Experiments were carried out on human ovarian carcinoma cells in four series: (1) control [Normoxia (5% CO2 in air), no treatment], (2) hypoxia (1% O2, 5% CO2, and 94% N2 for 48 h), (3) treatment with ASO targeted to HIF1A (48 h), and (4) combined action of hypoxia and ASO [14].
• We further demonstrate that a hydroxylase inhibitor, hypoxia, and desferrioxamine promote the functional and physical interaction between HIF-1 alpha CAD and p300/CBP in vivo [15].
• Recently we have demonstrated that sodium arsenite induces the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) protein and vascular endothelial growth factor (VEGF) in OVCAR-3 human ovarian cancer cells [16].
• We show here in both pancreatic and prostate carcinoma cell lines cobalt chloride (used to mimic hypoxia) -induced VEGF expression requires Src activation and leads to increased steady-state levels of HIF-1alpha and increased phosphorylation of signal and transducer of transcription 3 (STAT3) [17].
• This study demonstrates a novel mechanism of EGF-induced VEGF and HIF-1alpha expression through production of H(2)O(2) and activation of AKT and p70S6K1 in human ovarian cancer cells [18].

Biological context of HIF1A

• The HIF1A gene was mapped to human chromosome 14q21-q24 and mouse chromosome 12 [19].
• The degradation requires formation of a multiprotein complex (VHLCBC) and hydroxylation of HIF1A proline residues via members of the egg-laying-defective nine (EGLN) family [1].
• The HIF1A gene encodes the HIF-1alpha subunit of hypoxia-inducible factor 1, a transcription factor that is essential for cardiovascular development and systemic O2 homeostasis [20].
• Expression of HIF1A and VHL was high at 7-9 wk of gestation, when oxygen tension is low, and decreased when placental oxygen tension increases (10-12 wk of gestation) [1].
• In this paper we report the assignment of Hif1a and HIF1A to mouse chromosome 12 and human chromosome 14, respectively [21].

Anatomical context of HIF1A

• At 10-12 wk, VHL appeared in cytotrophoblast cells, which coincided with the disappearance of HIF1A [1].
• HIF1A was assigned to human chromosome 14q21-q24 by analysis of somatic cell hybrids and by fluorescence in situ hybridization [21].
• Here we report that expression of HIF-1 alpha is increased in diverse Epstein-Barr virus (EBV)-infected type II and III cell lines, which express EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein, as well as other latency proteins, but not in the parental EBV-negative cell lines [22].
• Degradation of HIF-1 alpha occurred mainly in the cytoplasm of HepG2 cells, whereas it occurs with equal efficiency in nuclear and cytoplasmic compartments of primary endothelial cells [23].
• Experiments in mouse fibroblast cell lines, lacking expression of c-Jun N-terminal kinases 1 and 2, suggested that these kinases are not required for induction of HIF-1alpha protein and VEGF mRNA [16].

Associations of HIF1A with chemical compounds

• Growth factor-mediated induction of HIF-1alpha was ablated by transient expression of a dominant negative form of Akt/PKB or by treatment with LY294002 [24].
• By using actinomycin D and cycloheximide we showed that A23187 induced HIF-1alpha mRNA expression, whereas BAPTA-am acted after transcription [25].
• Coimmunoprecipitation and glutathione S-transferase pull downs indicated that PI does not disrupt interactions between HIF-1 alpha and p300 [26].
• PI specifically inhibited the HIF-1 alpha CAD despite activating the HIF-1 alpha coactivator p300 and another p300 cysteine/histidine-rich domain 1-dependent transcription factor, STAT-2 [26].
• Although A23187 induced a striking and stable induction of HIF-1alpha, BAPTA-am only mediated a fast and transient increase [25].
• In clear cell RCC, HIF-1 alpha was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family [27].
• These stimulatory effects were abrogated by cotransfection with either HIF-1 alpha siRNA or treatment with resveratrol [28].
• All of these results indicate that Akt/mTOR-dependent translation of HIF-1alpha plays a critical role in the postirradiation up-regulation of intratumoral HIF-1 activity in response to radiation-induced alterations of glucose and oxygen availability in a solid tumor [29].

Physical interactions of HIF1A

• Interestingly, the VHL binding site within HIF-1 alpha overlapped with one of the minimal transactivation domains [30].
• We report here that insulin shares with hypoxia the ability to induce the HIF-1alpha/ARNT transcription complex in various cell types [31].
• Using the yeast two-hybrid screening system, we found that the inhibitory domain of HIF-1alpha strongly interacted with the C-terminal domain of histone deacetylase (HDAC) 7 [32].
• In contrast, the dephosphorylated HIF-1alpha was the major form that bound to p53 [33].
• The activity of HIF-1alpha is regulated by binding to the transcriptional co-activator cAMP-response element-binding protein-binding protein (CBP)/p300 [32].

Enzymatic interactions of HIF1A

• Our results indicate that the functions of HIF-1alpha varied with its phosphorylation status and that dephosphorylated HIF-1alpha mediated apoptosis by binding to and stabilizing p53 [33].
• Hypoxia-inducible factor 1 (HIF-1) is a phosphorylated protein and its phosphorylation is involved in HIF-1alpha subunit stabilization as well as in the regulation of HIF-1 transcriptional activity [34].
• These findings suggest that ubiquitination of HIF-1alpha is a dynamic process and that ubiquitinated HIF-1alpha might be rescued from degradation by VDU2 through deubiquitination [35].
• HIF-1alpha-specific prolyl hydroxylase and factor inhibiting HIF-1alpha (FIH-1) catalyze hydroxylation of the proline and asparagine residues of HIF-1alpha, respectively [36].

Co-localisations of HIF1A

• The HIF-target gene VEGF colocalized with HIF-1alpha protein in glomeruli and medullary collecting ducts [37].

Regulatory relationships of HIF1A

• We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells [38].
• Western blot assays demonstrated that, in a normoxic environment, PTEN downregulates HIF-1 alpha [39].
• Ectopic expression of EGLN1 inhibited HIF-1alpha transcriptional activity without altering its protein levels in a von Hippel-Lindau-deficient cell line, indicating a discrete activity of EGLN1 in transcriptional repression [40].
• Interestingly, FOXO4 down-regulates the HIF-1 alpha protein levels, consistent with the lack of hypoxia responsiveness [41].
• Ectopically expressed ARNT was consistently able to enhance HIF-1alpha phosphorylation in a binding-dependent manner [33].
• The paralogs SSAT1 and SSAT2 play complementary roles in promoting O(2)-independent and O(2)-dependent degradation of HIF-1alpha [42].

Other interactions of HIF1A

• Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT [31].
• Their sequences are conserved between HLF and HIF1alpha [43].
• HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia [44].
• Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300 [43].
• DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX [45].
• Inhibition of ERK1/2 signaling using U0126 enhanced HIF-1alpha stabilization, implicating ERK1/2 dephosphorylation as a contributing mechanism in NO-mediated HIF-1alpha activation [46].

Analytical, diagnostic and therapeutic context of HIF1A

• Expression of caspase 9 and HIF1A protein was confirmed by Western blotting [14].
• Relative quantification of EPO, VEGF and HIF1A mRNAs, based on the TaqMan reverse transcription-polymerase chain reaction (RT-PCR), was performed on autopsy tissue specimens from the heart (n = 10), brain (n = 10), kidney (n = 16) and lung (n = 8) after preservation at room temperature for various storage times [47].
• Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts [48].
• Immunofluorescence studies revealed that the HBx-induced HIF-1alpha was partially translocated into the nucleus in majority of cells while additional CoCl2-induced hypoxic condition caused complete nuclear translocation [49].
• NPR(-) cells lacked EPO induction under hypoxia, and HIF-1alpha in NPR(-) cells did not respond to either transcriptional activation or translocation to the nucleus based on electrophoretic mobility shift assays and reporter gene assay including hypoxia response element [50].

References