HIF1A: Difference between revisions

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Bruno Prado Eleuterio, Milena Grigoriou, Michal Harel

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 == Introduction ==
-HIF1α is a subunit of the transcription factor HIF1, together with HIF1β. HIF1α is part exclusively of HIF1 whilst HIF1β is part of other transcription factors as well as HIF1.
+HIF1α is a subunit of the transcription factor HIF1, together with HIF1β <ref name="Neill>O’Neill, Luke A. J., Rigel J. Kishton, and Jeff Rathmell. 2016. “A Guide to Immunometabolism for Immunologists.” Nature Reviews Immunology 16 (9): 553–65. https://doi.org/10.1038/nri.2016.70.
-HIF1 is related to glucose metabolism and it was first described in hypoxia conditions, but it is now known that it can be activated also in normoxia situations, acting especially in the polarization of immune cells to more inflammatory phenotypes.
+</ref>. HIF1α is part exclusively of HIF1 whilst HIF1β is part of other transcription factors as well as HIF1.
+HIF1 is related to glucose metabolism, stimulation of circulation and it was first described in hypoxia conditions, but it is now known that it can be activated also in normoxia situations, acting especially in the polarization of immune cells to more inflammatory phenotypes <ref name="Neill">.
 == Structure ==
-The N-terminal region of HIF1α contains a basic helix-loop-helix (bHLH) structure and a PERARNT-SIM (PAS) domain that are responsible for dimerization with HIF1β and interaction with the hypoxia responsive elements (HRE) [5’-(G/C/T)-ACGTGC- (G/T)-3’] present in many enhancers regions of different genes. HIF1α also contains a transactivation domain (TAD) that interacts with CREB binding protein (CBP) and p300, transcription co-activators. TAD can suffer hydroxylation that inhibits the interaction between these co-activating factors and marks the subunit to ubiquitination and consequently degradation in the proteasome.
+The N-terminal region of HIF1α contains a basic helix-loop-helix (bHLH) structure, that is responsible for the interaction with the hypoxia responsive elements (HRE) [5’-(G/C/T)-ACGTGC- (G/T)-3’] present in many enhancers regions of different genes, and a PERARNT-SIM (PAS) domain that are responsible for dimerization with HIF1β. HIF1β is also known as aryl hydrocarbon receptor nuclear translocator (ARNT) <ref name= "Loboda">Loboda, Agnieszka, Alicja Jozkowicz, and Jozef Dulak. 2010. “HIF-1 and HIF-2 Transcription Factors — Similar but Not Identical.” Molecules and Cells 29 (5): 435–42. https://doi.org/10.1007/s10059-010-0067-2.</ref>.
+HIF1α also contains a transactivation domain (TAD) that interacts with CREB binding protein (CBP) and p300, transcription co-activators. In sufficient O2 concentration <ref name="Yang">YANG, Chao, Zhang-Feng ZHONG, Sheng-Peng WANG, Chi-Teng VONG, Bin YU, and Yi-Tao WANG. 2021. “HIF-1: Structure, Biology and Natural Modulators.” Chinese Journal of Natural Medicines 19 (7): 521–27. https://doi.org/10.1016/s1875-5364(21)60051-1.
-A região N-terminal de HIF1α contém uma região de helix-loop-helix básica (bHLH) e um domínio PAS (PERARNT-SIM) que são responsáveis pela dimerização com HIF1β e interação com DNA.
+</ref>, TAD can suffer hydroxylation by prolyl-hydroxylase (PHD) proteins, which inhibits the interaction between those co-activating factors and marks the subunit to ubiquitination by von Hippel-Lindau tumor suppressor protein (VHL), part of the E3 ubiquitin-protein ligase, and consequently degradation in the proteasome. Other interactions with different groups can inhibit the activity of HIF1α as well <ref name="Watts">Watts, Emily R., and Sarah R. Walmsley. 2019. “Inflammation and Hypoxia: HIF and PHD Isoform Selectivity.” Trends in Molecular Medicine 25 (1): 33–46. https://doi.org/10.1016/j.molmed.2018.10.006.
-HIF-1 reconhece o elemento responsivo a hipóxia (HRE) [5’-(G/C/T)-ACGTGC- (G/T)-3’] presente nos enhancers de muitos genes.
+</ref>.
-A subunidade HIF1α contém dois domínios TAD (transactivation domain) que interagem com CBP (CREB binding protein) e p300, co-ativadores de transcrição na região C-terminal do TAD (CTAD). Essa região sofre hidroxilação o que impede a interação entre os fatores de co-ativação e também marca a subunidade para ubiquitinação e consequente degradação pelo proteassoma.
 == Function ==
-HIF1α is one of the subunits of HIF1. HIF1 is a transcription factor that binds to HREs in the genome sequence and regulates genes involved in angiogenesis, vascular regulation, erythropoiesis, iron metabolism, cellular growth, apoptosis, extracellular matrix metabolism and glycolysis <ref> Watts, Emily R., and Sarah R. Walmsley. 2019. “Inflammation and Hypoxia: HIF and PHD Isoform Selectivity.” Trends in Molecular Medicine 25 (1): 33–46. https://doi.org/10.1016/j.molmed.2018.10.006. </ref>.  Although it was first described in hypoxia situations, it is now known to be active in normoxia situations as well
+HIF1α is one of the subunits of HIF1. HIF1 is a transcription factor that binds to HREs in the genome sequence and regulates genes involved in angiogenesis, vascular regulation, erythropoiesis, iron metabolism, cellular growth, apoptosis, extracellular matrix metabolism and glycolysis <ref name="Watts"/>.  Although it was first described in hypoxia situations, it is now known to be active in normoxia situations as well
-<ref>O’Neill, Luke A. J., Rigel J. Kishton, and Jeff Rathmell. 2016. “A Guide to Immunometabolism for Immunologists.” Nature Reviews Immunology 16 (9): 553–65. https://doi.org/10.1038/nri.2016.70.
+<ref name="Neill">O’Neill, Luke A. J., Rigel J. Kishton, and Jeff Rathmell. 2016. “A Guide to Immunometabolism for Immunologists.” Nature Reviews Immunology 16 (9): 553–65. https://doi.org/10.1038/nri.2016.70.
 </ref> .
-In hypoxia, the PHDs mark HIF1α to ubiquitination and consequently degradation in the proteasome complex. This process occurs when molecular oxygen (O2) is present <ref> Watts, Emily R., and Sarah R. Walmsley. 2019. “Inflammation and Hypoxia: HIF and PHD Isoform Selectivity.” Trends in Molecular Medicine 25 (1): 33–46. https://doi.org/10.1016/j.molmed.2018.10.006. </ref>.
+In hypoxia, the PHDs mark HIF1α to ubiquitination and consequently degradation in the proteasome complex. This process occurs when molecular oxygen (O2) is present <ref name="Watts"/>.
-In immune cells, HIF1 can be activated in normoxia and its effect in the regulation of glycolysis is directly linked to their polarization, contributing to an inflammatory profile <ref>O’Neill, Luke A. J., Rigel J. Kishton, and Jeff Rathmell. 2016. “A Guide to Immunometabolism for Immunologists.” Nature Reviews Immunology 16 (9): 553–65. https://doi.org/10.1038/nri.2016.70.
+In immune cells, HIF1 can be activated in normoxia and its effect in the regulation of glycolysis is directly linked to their polarization, contributing to an inflammatory profile <ref name="Neil"/>.
-</ref>.
 == Disease ==