Analysis of hypoxia inducible factor 1 alpha subunit (HIF1A)- and endothelial PAS domain protein 1 (EPAS1)-dependent transcriptomes in human HepG2 hepatocellular carcinoma cells
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HIF1A
PAS domain
Hypoxia-Inducible Factors
Hypoxia-Inducible Factor 1
Alpha (finance)
Hypoxia
Hypoxia-inducible factor-1alpha (HIF-1α) is a major transcription factor that adapts to low oxygen homeostasis and regulates the expression of several hypoxic genes, which aid in cancer survival and development. It has recently piqued the interest of translational researchers in the disciplines of cancer sciences. Hypoxia triggers an ample adaptive mechanism mediated via the HIF-1α transcriptional domain. Anaerobic glycolysis, angiogenesis, metastasis, and mitophagy are adaptive mechanisms that support tumor survival by promoting oxygen supply and regulating oxygen demand in hypoxic tumor cells. Throughout this pathway, the factor-inhibiting HIF-1α is a negative regulator of HIF-1α leading to its hydroxylation at the C-TAD domain of HIF-1α under normoxia. Thus, hydroxylated HIF-1α is unable to proceed with the transcriptional events due to interference in binding of C-TAD and CBP/p300. From this review, we can hypothesize that remodeling of FIH-1 activity is a unique mechanism that decreases the transcriptional activity of HIF-1α and, as a result, all of its hypoxic consequences. Hence, this review manuscript details the depth of knowledge of FIH-1 on hypoxia-associated cellular and molecular events, a potential strategy for targeting hypoxia-induced malignancies.
Hypoxia-Inducible Factor 1
HIF1A
Hypoxia-Inducible Factors
Hypoxia
PAS domain
Tumor progression
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Abstract Hypoxia-inducible transcription factors (HIF) form heterodimeric complexes that mediate cell responses to hypoxia. The oxygen-dependent stability and activity of the HIF-α subunits is traditionally associated to post-translational modifications such as hydroxylation, acetylation, ubiquitination and phosphorylation. Here we report novel evidence showing that unsaturated fatty acids are naturally occurring, non-covalent structural ligands of HIF-3α, thus providing the initial framework for exploring its exceptional role as a lipid sensor under hypoxia.
Hypoxia-Inducible Factor 1
Hydroxylation
PAS domain
Hypoxia-Inducible Factors
Hypoxia
Post-translational regulation
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HIF1A
PAS domain
Hypoxia-Inducible Factor 1
Hypoxia
Hypoxia-Inducible Factors
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HIF1A
PAS domain
Hypoxia-Inducible Factors
Hypoxia-Inducible Factor 1
Alpha (finance)
Hypoxia
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HIF1A
PAS domain
Hypoxia-Inducible Factors
Hypoxia
Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factors
Hypoxia-Inducible Factor 1
Hypoxia
HIF1A
Homeostasis
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HIF1A
Hypoxia
Hypoxia-Inducible Factors
Hypoxia-Inducible Factor 1
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Oxygen is necessary for most life on our planet, and the ability to sense and adapt to changes in oxygen concentration is required for life to persist. Hypoxia is defined as the deficiency of oxygen reaching body tissues. In mammals, tissue response to hypoxia is integral to a wide variety of processes, including the building of vasculature, heart disease, and tumor angiogenesis. The transcriptional response to hypoxia is largely regulated by hypoxia inducible factors (HIFs). These HIFs are heterodimeric, consisting of an oxygen-sensing alpha subunit and a non-oxygen-sensing beta subunit. When oxygen levels are normal, HIF-1 alpha is hydroxylated by EGLN/PHD prolyl hydroxylases. This modification targets HIF-1alpha for degradation via the von Hippel Lindau tumor suppressor protein (VHL). Oxygen is an essential substrate for EGLN/PHD activity, and during hypoxia, the HIF-1 alpha subunit is not hydroxylated, and is, therefore, stable. HIF-1 alpha translocates to the nucleus, where it regulates the transcription of downstream genes. This pathway is evolutionarily conserved between mammals and Caenorhabditis elegans, where genes encode homologs of HIF-1 alpha, PHD/EGLN and VHL as HIF-1, EGL-9 and VHL-1, respectively. Working on C. elegans, our lab is attempting to find negative regulators of the HIF-1 pathway by performing a forward genetic screen and identifying mutations that cause increased expression of a HIF-1-responsive reporter gene. I have shown progress in mapping these potential positive regulator mutations and in attempting to prioritize mutations obtained in the screen by molecular analysis of various RNA transcripts and protein levels. In addition, I tested a hypothesis that a novel ubiquitin-degradation pathway that is independent of VHL-1 contributed to HIF-1 regulation.
Hypoxia-Inducible Factor 1
HIF1A
Hypoxia-Inducible Factors
Genetic screen
PAS domain
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HIF1A
Hypoxia
Hypoxia-Inducible Factors
Hypoxia-Inducible Factor 1
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HIF1A
Hypoxia-Inducible Factors
Hypoxia-Inducible Factor 1
Hypoxia
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