Disease relevance of SETD2

• HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus [1].
• BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases [2].
• Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters [3].
• Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult [3].
• In addition to the HIF-1 complex, hepatocyte nuclear factor 4alpha (HNF4alpha) was found to be indispensable for hypoxia-induced EPO gene expression in hepatoma cells [4].

Psychiatry related information on SETD2

• Considering that activation of HIF-1 provokes pro-survival as well as pro-death decisions under hypoxia, it will be crucial to understand decision making processes in regulating cell death, adaptation and chemoresistance [5].
• 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 [6].

High impact information on SETD2

• Hypoxia-inducible factor 1 (HIF-1) is a global regulator of cellular and systemic O(2) homeostasis in animals [1].
• Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating early cellular responses to hypoxia [7].
• HIF-1 alpha is the oxygen-regulated subunit of HIF-1, an alpha beta heterodimeric complex [8].
• The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing [9].
• HIF-1 alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased [10].

Chemical compound and disease context of SETD2

• The Abeta-induced changes in glucose metabolism are due to the activation of the transcription factor hypoxia inducible factor 1 (HIF-1) [11].
• Taken together, these results demonstrate that hypoxia induces leukocyte beta2 integrin expression and function by transcriptional mechanisms dependent upon HIF-1 [12].
• HIF-1 DNA-binding activity is induced by hypoxia or cobalt chloride treatment of Hep3B cells [13].
• We conclude that during hypoxia, an increase in intracellular Ca(2+) activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription [14].
• Transfection experiments with wild-type and hypoxia response element (HRE)-mutated PAI promoter constructs revealed that the HRE binding hypoxiainducible factor-1 (HIF-1) mediated the response to A23187 and BAPTA-am [15].

Biological context of SETD2

• Thus, our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD [16].
• In this report we describe how this hypoxic environment can be used to activate heterologous gene expression driven by a hypoxia-responsive element (HRE), which interacts with the transcriptional complex hypoxia-inducible factor-1 (HIF-1) [17].
• Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis [9].
• Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours [9].
• Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation [9].

Anatomical context of SETD2

• Although HYPB and HYPC are novel, HYPA is human FBP-11, a protein implicated in spliceosome function [18].
• These data suggest that the oxygen-regulated early events of trophoblast differentiation are in part mediated by TGFbeta(3) through HIF-1 transcription factors [19].
• In this paper, we demonstrate that HIF-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed [20].
• Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells [21].
• Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis [22].

Associations of SETD2 with chemical compounds

• HIF-1 thus appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology [10].
• The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide [11].
• YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, an agent developed for circulatory disorders that inhibits platelet aggregation and vascular contraction, inhibits HIF-1 activity in vitro [23].
• Surprisingly, the CH1 domain was only required for an average of approximately 35-50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA(S)) accounts for approximately 70% [24].
• These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family [25].

Physical interactions of SETD2

• Identification of the full-length huntingtin- interacting protein p231HBP/HYPB as a DNA-binding factor [26].
• The hypoxia-inducible factor-1 (HIF-1) binding site located at approximately -1 kbp in the VEGF promoter was not required for down-regulation of promoter activity by gefitinib under normoxia [27].
• Chromatin immunoprecipitation (ChIP) and sequential ChIP (re-ChIP) analysis showed that both Brm and Brg-1 associate with the enhancer region of the EPO gene in vivo in a hypoxia-dependent fashion and that each is present in a complex with HIF-1 [28].
• Our data show that extracellular acidosis increased the level of CA IX protein, mRNA and the activity of minimal CA9 promoter that contains binding sites for HIF-1 and SP-1 transcription factors [29].
• Expression of hypoxia-responsive genes is mediated by the heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) in complex with the p300/CREB-binding protein (p300/CBP) transcriptional coactivator [30].

Enzymatic interactions of SETD2

• 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 [31].

Regulatory relationships of SETD2

• These findings reveal that CITED2 regulates HIF-1 by competing for a hot spot on the p300 CH1 domain [30].
• Moreover, LMP1 induces HIF-1 DNA binding activity and upregulates HRE and VEGF promoter transcriptional activity [32].
• Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia [33].
• Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene [34].
• Moreover, HIF-1-deficient hepatoma cell (Hepa1 c4) and its wild-type counterpart (Hepa1 c1c4) up-regulates Ang2 during hypoxia [35].

Other interactions of SETD2

• Here we report the structural and functional characterization of the huntingtin interacting protein B (HYPB) [16].
• 3) Coimmunoprecipitation assays indicate that HYPB protein associates with hyperphosphorylated RNA polymerase II (RNAPII) but not the unphosphorylated form [16].
• Interestingly, PHD2 is upregulated by hypoxia, providing an HIF-1-dependent auto-regulatory mechanism driven by the oxygen tension [36].
• The protein CITED2, which binds p300/CBP, is thought to be a negative regulator of HIF-1 transactivation [30].
• Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain [37].

Analytical, diagnostic and therapeutic context of SETD2

• Its expression, which is regulated by the HIF-1 transcription factor, is strongly induced by hypoxia and correlates with a poor response to classical chemo- and radiotherapies [38].
• Western blot analysis revealed that the amount of the beta subunit of HIF-1, identical to aryl hydrocarbon receptor nuclear translocator 1 (ARNT1), and the homolog ARNT2 increased in nuclear extracts from SH-SY5Y cells exposed to anoxia [4].
• In electrophoretic mobility shift assays, affinity-purified IgY antibody was shown to recognize the native HIF-1 (but not the related HIF-2) complex that specifically binds an oligonucleotide containing the HIF-1 DNA binding site [39].
• One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity [40].
• These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients [41].

References