HIF1A

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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. 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

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 ^[3]. Although it was first described in hypoxia situations, it is now known to be active in normoxia situations as well ^[4] . In hypoxia, the PHDs mark HIF1α to ubiquitination and consequently degradation in the proteasome complex. This process occurs when molecular oxygen (O2) is present ^[5]. 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 ^[6].

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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