Bruno Prado/Sandbox1
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==Introduction== | ==Introduction== | ||
| - | <StructureSection load=' | + | <StructureSection load='1H2K' size='340' side='right' caption='Caption for this structure' scene=''> |
| - | HIF1α is a subunit of the transcription factor HIF1, together with HIF1β | + | HIF1α is a subunit of the transcription factor HIF1, together with HIF1β <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 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 | + | 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="oneill">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>. |
== Structure == | == Structure == | ||
| - | 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) | + | 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"/>. |
| - | HIF1α also contains a transactivation domain (TAD) that interacts with CREB binding protein (CBP) and p300, transcription co-activators. In sufficient O2 concentration | + | HIF1α also contains a transactivation domain (TAD) that interacts with CREB binding protein (CBP) and p300, transcription co-activators. In sufficient O2 concentration<ref>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.</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.</ref>. |
== Function == | == 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 | + | 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 name="oneill"/>. |
| - | In hypoxia, the PHDs mark HIF1α to ubiquitination and consequently degradation in the proteasome complex. This process occurs when molecular oxygen (O2) is present | + | 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 | + | 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="oneill"/>. |
== Disease == | == Disease == | ||
| - | Hypoxia-inducible factors (HIFs) are essential in the progression of various diseases, including cancer and conditions such as peripheral arterial disease, pulmonary arterial hypertension, and sleep apnea. They also play a significant role in regulating insulin signaling and obesity. | + | Hypoxia-inducible factors (HIFs) are essential in the progression of various diseases, including cancer and conditions such as peripheral arterial disease, pulmonary arterial hypertension, and sleep apnea. They also play a significant role in regulating insulin signaling and obesity<ref>Feng, Zhihui, Xuan Zou, Yaomin Chen, Hanzhi Wang, Yingli Duan, and Richard K Bruick. 2018. “Modulation of HIF-2α PAS-B Domain Contributes to Physiological Responses.” Proceedings of the National Academy of Sciences of the United States of America 115 (52): 13240–45. https://doi.org/10.1073/pnas.1810897115.</ref>. |
| - | Under hypoxic conditions, HIFs are stabilized and activate the expression of genes related to cellular adaptation to oxygen deprivation. In the presence of oxygen, HIFs are degraded, but during hypoxia, they form active complexes and promote important cellular changes. | + | Under hypoxic conditions, HIFs are stabilized and activate the expression of genes related to cellular adaptation to oxygen deprivation. In the presence of oxygen, HIFs are degraded, but during hypoxia, they form active complexes and promote important cellular changes <ref name="cowman">Cowman, Sophie J., and Mei Yee Koh. 2022. “Revisiting the HIF Switch in the Tumor and Its Immune Microenvironment.” Trends in Cancer 8 (1): 28–42. https://doi.org/10.1016/j.trecan.2021.10.004.</ref>. |
| - | Hypoxia is a common feature in solid tumors and their metastases, leading to the activation of HIFs, which influence gene expression in both tumor cells and immune cells in the tumor microenvironment. This affects tumor progression and treatment response. | + | Hypoxia is a common feature in solid tumors and their metastases, leading to the activation of HIFs, which influence gene expression in both tumor cells and immune cells in the tumor microenvironment. This affects tumor progression and treatment response <ref name="cowman"/>. |
| - | In particular, HIF-1α is crucial in the initiation of certain types of cancer, such as clear cell renal cell carcinoma (ccRCC), and is elevated in pre-neoplastic stages. | + | In particular, HIF-1α is crucial in the initiation of certain types of cancer, such as clear cell renal cell carcinoma (ccRCC), and is elevated in pre-neoplastic stages <ref name="cowman"/>. |
== Structural highlights == | == Structural highlights == | ||
| - | + | The HIF1α binding site to HRE is the <scene name='10/1052399/Bhlh/4'>bHLH domain</scene> (in red), this domain is responsible for the interaction between the transcription factor and the DNA, leading to the active function of HIF1α: to increase mRNA synthesis of the target genes. The <scene name='10/1052399/Nodd/1'>NODD</scene> (N-terminal oxygen dependent degradation domain), also known as N-TAD (N-terminal transactivation domain) is where the hydroxylation of HIF1α occurs, by the prolyl-hydroxylase enzymes (PHDs), targeting the transcription factor to degradation via pVHL, ubiquitination and proteasome. | |
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Introduction
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References
- ↑ 1.0 1.1 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.
- ↑ 2.0 2.1 2.2 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.
- ↑ 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.
- ↑ 4.0 4.1 4.2 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.
- ↑ Feng, Zhihui, Xuan Zou, Yaomin Chen, Hanzhi Wang, Yingli Duan, and Richard K Bruick. 2018. “Modulation of HIF-2α PAS-B Domain Contributes to Physiological Responses.” Proceedings of the National Academy of Sciences of the United States of America 115 (52): 13240–45. https://doi.org/10.1073/pnas.1810897115.
- ↑ 6.0 6.1 6.2 Cowman, Sophie J., and Mei Yee Koh. 2022. “Revisiting the HIF Switch in the Tumor and Its Immune Microenvironment.” Trends in Cancer 8 (1): 28–42. https://doi.org/10.1016/j.trecan.2021.10.004.
