scholarly journals HIFα as a target for different oncoproteins during carcinogenesis

2019 ◽  
Vol 5 (4) ◽  
pp. 64-71
Author(s):  
V. A. Kobliakov
Keyword(s):  
Hypoxia Inducible Factor ◽  
Common Element ◽  
Tissue Respiration ◽  
Tumour Development ◽  
Signal Systems ◽  
Intercellular Matrix ◽  
Carcinogenic Action ◽  
Basic Characteristics ◽  
Factor Α ◽  
Hypoxic State

The basic characteristics of tumours are ability for invasiveness and metastasis. These properties are realized due to destruction of intercellular matrix caused with acidification of intercellular area stimulated with transition from tissue respiration to glycolysis. The transition  to glycolysis in tumor cells is observed not only during hypoxic state how is realized in normal cells but also during oxygenation (Warburg  effect). It is accepted that by any carcinogenic action the activation of oncogenes or inactivation of genes – supressors occurs. As a result  it is permanent expression of oncoproteins and stimulation of tumour development. Different oncoproteins operate in different regulation systems at that they cause the same effect – tumour development.It is assumed that oncoproteins are not the ultimate factor in tumour development but there are existed some common element which is activated by different oncoproteins. In this review it is assumed that common element is HIFα (hypoxia-inducible factor α) transcription factor and it is discussed the mechanisms its activation by oncoproteins takes place in different signal systems.

scholarly journals Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

2019 ◽  
Vol 116 (48) ◽  
pp. 24006-24011 ◽  
Author(s):  
Tom D. Brutsaert ◽  
Melisa Kiyamu ◽  
Gianpietro Elias Revollendo ◽  
Jenna L. Isherwood ◽  
Frank S. Lee ◽  
...  
Keyword(s):  
Natural Selection ◽  
Aerobic Capacity ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Total Sample ◽  
Causal Variant ◽  
Analysis Of Covariance ◽  
Adaptation To Hypoxia ◽  
Spurious Association ◽  
Factor Α

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min−1 and mL⋅min−1⋅kg−1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min−1⋅kg−1 vs. CC = 30.5 mL⋅min−1⋅kg−1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.

Anterior Diffuse Retinoblastoma: Mutational Analysis and Immunofluorescence Staining

2009 ◽  
Vol 133 (8) ◽  
pp. 1215-1218
Author(s):  
Michelle B. Crosby ◽  
G. Baker Hubbard ◽  
Brenda L. Gallie ◽  
Hans E. Grossniklaus
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mutational Analysis ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β ◽  
Immunofluorescence Staining ◽  
Vascular Endothelial ◽  
Factor Α ◽  
Oxide Synthase ◽  
Endothelial Growth Factor

Abstract Retinoblastoma is the most common primary intraocular tumor of childhood and may be heritable or occur sporadically. Anterior diffuse retinoblastoma is an uncommon variant that is thought to be sporadic. We describe a child with anterior diffuse retinoblastoma who presented with a pseudohypopyon. Genetic analysis showed a germline mutation of the RB1 allele that is potentially heritable. Immunofluorescence staining was positive for transforming growth factor β and for vascular endothelial growth factor and negative for inducible nitric oxide synthase and for hypoxia inducible factor α in the tumor seeds, indicating acquisition of nonischemia-mediated survival factors of the tumor seeds in the aqueous humor.

mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats

2021 ◽  
Author(s):  
Demet Sinem Guden ◽  
Meryem Temiz-Resitoglu ◽  
Sefika Pınar Senol ◽  
Deniz Kibar ◽  
Sakir Necat Yilmaz ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microglial Activation ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Systemic Inflammatory Response ◽  
Mtor Inhibition ◽  
Factor Α

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS). Rats received saline (10 ml/kg), LPS (10 mg/kg), and/or rapamycin (1 mg/kg) via intraperitoneally. Inhibition of mTOR by rapamycin blocked phosphorylated form of ribosomal protein S6, NF-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, the inducible nitric oxide synthase, gp91<sup>phox</sup>, and p47<sup>phox</sup> in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while increased expression of B-cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.

scholarly journals Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer

2020 ◽  
Vol 205 (8) ◽  
pp. 2301-2311
Author(s):  
Kayla J. Steinberger ◽  
Mary A. Forget ◽  
Andrey A. Bobko ◽  
Nicole E. Mihalik ◽  
Marieta Gencheva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hypoxia Inducible Factor ◽  
Factor Α ◽  
Α Subunits

scholarly journals HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 134 ◽  
Author(s):  
Mohamed M. Ali ◽  
Shane A. Phillips ◽  
Abeer M. Mahmoud
Keyword(s):  
Dna Methylation ◽  
Interleukin 1 ◽  
Hypoxia Inducible Factor ◽  
Interferon Γ ◽  
The Body ◽  
Human Adipocytes ◽  
Protein Levels ◽  
Factor Α ◽  
Necrosis Factor

Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 μM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 μM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1β, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.

scholarly journals Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation

2006 ◽  
Vol 12 (18) ◽  
pp. 5384-5394 ◽  
Author(s):  
Dylan T. Jones ◽  
Christopher W. Pugh ◽  
Simon Wigfield ◽  
Malcolm F.G. Stevens ◽  
Adrian L. Harris
Keyword(s):  
Dna Binding ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Factor Α

scholarly journals Regulation of the Drosophila Hypoxia-Inducible Factor α Sima by CRM1-Dependent Nuclear Export

2008 ◽  
Vol 28 (10) ◽  
pp. 3410-3423 ◽  
Author(s):  
Nuria M. Romero ◽  
Maximiliano Irisarri ◽  
Peggy Roth ◽  
Ana Cauerhff ◽  
Christos Samakovlis ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Cellular Responses ◽  
Site Directed Mutagenesis ◽  
Transcriptional Coactivator ◽  
Nuclear Retention ◽  
Helix Loop Helix ◽  
Localization Signal ◽  
Factor Α

ABSTRACT Hypoxia-inducible factor α (HIF-α) proteins are regulated by oxygen levels through several different mechanisms that include protein stability, transcriptional coactivator recruitment, and subcellular localization. It was previously reported that these transcription factors are mainly nuclear in hypoxia and cytoplasmic in normoxia, but so far the molecular basis of this regulation is unclear. We show here that the Drosophila melanogaster HIF-α protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified the relevant nuclear localization signal and two functional nuclear export signals (NESs). These NESs are in the Sima basic helix-loop-helix (bHLH) domain and promote CRM1-dependent nuclear export. Site-directed mutagenesis of either NES provoked Sima nuclear retention and increased transcriptional activity, suggesting that nuclear export contributes to Sima regulation. The identified NESs are conserved and probably functional in the bHLH domains of several bHLH-PAS proteins. We propose that rapid nuclear export of Sima regulates the duration of cellular responses to hypoxia.

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