HIF1A

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1 Introduction
2 Structure
3 Function
4 Disease
5 Structural highlights

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. 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.

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.

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.

HIF-1 reconhece o elemento responsivo a hipóxia (HRE) [5’-(G/C/T)-ACGTGC- (G/T)-3’] presente nos enhancers de muitos genes. 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

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. 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. 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. 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.

Structural highlights

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References

Alves, Cinthia C, Eduardo A Donadi, and Silvana Giuliatti. 2021. “Structural Characterization of the Interaction of Hypoxia Inducible Factor-1 with Its Hypoxia Responsive Element at the −964G > a Variation Site of the HLA-G Promoter Region.” International Journal of Molecular Sciences 22 (23): 13046–46. https://doi.org/10.3390/ijms222313046.

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644

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. Dengler, Veronica L., Matthew D. Galbraith, and Joaquín M. Espinosa. 2013. “Transcriptional Regulation by Hypoxia Inducible Factors.” Critical Reviews in Biochemistry and Molecular Biology 49 (1): 1–15. https://doi.org/10.3109/10409238.2013.838205. 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. “HIF Enhancer Pathways.” 2017. Www.rndsystems.com. R&D Systems. 2017. https://www.rndsystems.com/pathways/hif-enhancer-pathways. “HIF Repressor Pathways.” 2017. Www.rndsystems.com. R&D Systems. 2017. https://www.rndsystems.com/pathways/hif-repress-pathways. Iyer, Narayan V, Sandra W Leung, and Gregg L Semenza. 1998. “The Human Hypoxia-Inducible Factor 1α Gene:HIF1AStructure and Evolutionary Conservation.” Genomics 52 (2): 159–65. https://doi.org/10.1006/geno.1998.5416. 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. Michel, G, E Minet, I Ernest, C Michiels, F Durant, and J Remacle. 1999. “Molecular Modeling of the Hypoxia-Inducible Factor-1 (HIF-1).” Theoretical Chemistry Accounts 101 (1-3): 51–56. https://doi.org/10.1007/s002140050405. 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. 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. 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. Ziello, Jennifer E, Ion S Jovin, and Yan Huang. 2007. “Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and Its Potential for Therapeutic Intervention in Malignancy and Ischemia.” The Yale Journal of Biology and Medicine 80 (2): 51–60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2140184/.

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HIF1A

From Proteopedia

Revision as of 19:34, 2 June 2024

Your Heading Here (maybe something like 'Structure')

Contents

Introduction

Structure

Function

Disease

Structural highlights

References

Proteopedia Page Contributors and Editors (what is this?)

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@@ Line 39: / Line 39: @@
 <references/>
+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.
+Dengler, Veronica L., Matthew D. Galbraith, and Joaquín M. Espinosa. 2013. “Transcriptional Regulation by Hypoxia Inducible Factors.” Critical Reviews in Biochemistry and Molecular Biology 49 (1): 1–15. https://doi.org/10.3109/10409238.2013.838205.
+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.
+“HIF Enhancer Pathways.” 2017. Www.rndsystems.com. R&D Systems. 2017. https://www.rndsystems.com/pathways/hif-enhancer-pathways.
+“HIF Repressor Pathways.” 2017. Www.rndsystems.com. R&D Systems. 2017. https://www.rndsystems.com/pathways/hif-repress-pathways.
+Iyer, Narayan V, Sandra W Leung, and Gregg L Semenza. 1998. “The Human Hypoxia-Inducible Factor 1α Gene:HIF1AStructure and Evolutionary Conservation.” Genomics 52 (2): 159–65. https://doi.org/10.1006/geno.1998.5416.
+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.
+Michel, G, E Minet, I Ernest, C Michiels, F Durant, and J Remacle. 1999. “Molecular Modeling of the Hypoxia-Inducible Factor-1 (HIF-1).” Theoretical Chemistry Accounts 101 (1-3): 51–56. https://doi.org/10.1007/s002140050405.
+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.
+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.
+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.
+Ziello, Jennifer E, Ion S Jovin, and Yan Huang. 2007. “Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and Its Potential for Therapeutic Intervention in Malignancy and Ischemia.” The Yale Journal of Biology and Medicine 80 (2): 51–60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2140184/.