HIF1AN Human
Description
Gene and Protein Architecture
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Transcripts: The HIF1AN gene produces five splice variants, with the canonical isoform (ENST00000299163.7) encoding a 349-amino-acid protein (40.2 kDa) .
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Domains: Contains a Fe²⁺- and 2-oxoglutarate-dependent dioxygenase domain, critical for hydroxylation activity .
Table 1: HIF1AN Transcript Variants
| Transcript ID | Biotype | Protein Length | Key Features |
|---|---|---|---|
| ENST00000299163.7 | Protein coding | 349 aa | Canonical isoform, MANE Select |
| ENST00000533589.6 | Protein coding | 191 aa | CDS 3' incomplete |
| ENST00000526476.5 | Nonsense-mediated decay | 35 aa | Non-functional |
Enzymatic Activity
HIF1AN hydroxylates an asparagine residue (Asn-803) in the C-terminal transactivation domain (CAD) of HIF-1α under normoxic conditions. This modification blocks the interaction between HIF-1α and transcriptional coactivators (e.g., p300/CBP), thereby suppressing hypoxia-responsive genes like VEGF and EPO .
Role in Cellular Hypoxia Response
HIF1AN fine-tunes the hypoxia-inducible factor pathway:
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Oxygen Sensing: Works alongside prolyl hydroxylases (PHDs) to regulate HIF-1α stability and activity .
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Cross-Talk with Other Pathways: Hydroxylates Notch intracellular domain (ICD), modulating neurogenesis and myogenesis .
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Iron Dependency: Requires Fe²⁺ and 2-oxoglutarate for enzymatic activity, linking its function to cellular iron metabolism .
Tumor Suppressor Activity
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Breast Cancer (BC):
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Low HIF1AN expression correlates with aggressive tumor progression, reduced survival (HR = 0.49 for OS; p < 0.001), and altered immune infiltration .
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Immune Modulation: High HIF1AN levels associate with increased infiltration of T helper cells (R = 0.33) and NK cells (R = 0.087), but reduced macrophages (R = -0.171) .
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Pancreatic and Colorectal Cancers: Overexpression linked to tumor aggressiveness, while inhibition shows therapeutic potential .
Table 2: HIF1AN Expression and Prognosis in Breast Cancer
Mechanistic Insights
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Tumor Microenvironment (TME): HIF1AN downregulation promotes angiogenesis via VEGF and fosters immunosuppression by recruiting tumor-associated macrophages (TAMs) .
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Subtype-Specific Effects: In HER2-positive BC, low HIF1AN predicts poor outcomes, whereas luminal subtypes show less dependency .
Recombinant HIF1AN Protein
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Applications: Used in research to study HIF-1α regulation and develop hypoxia-targeted therapies .
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Specifications: 40.2 kDa recombinant protein expressed in E. coli, purified via chromatographic techniques .
Targeting HIF1AN in Disease
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Cancer: Small-molecule inhibitors of HIF1AN could stabilize HIF-1α in ischemic conditions, while activators might suppress oncogenic HIF signaling .
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Chronic Wounds: HIF1AN activation enhances skin regeneration in diabetic mice, suggesting potential for wound-healing therapies .
Future Directions
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Biomarker Development: Validation of HIF1AN as a prognostic marker in multicenter trials.
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Gene Editing: CRISPR-based modulation to explore its role in immune evasion and metastasis.
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Combination Therapies: Pairing HIF1AN regulators with checkpoint inhibitors (e.g., anti-PD-1) to enhance antitumor immunity .
Product Specs
Product Science Overview
Hypoxia-Inducible Factor-1 Alpha (HIF-1α) is a crucial transcription factor that plays a significant role in cellular response to low oxygen levels (hypoxia). It is a subunit of the heterodimeric transcription factor HIF-1, which is composed of HIF-1α and the aryl hydrocarbon receptor nuclear translocator (ARNT or HIF-1β). HIF-1α is encoded by the HIF1A gene and is considered the master regulator of the cellular and developmental response to hypoxia .
HIF-1α contains several important domains, including a basic helix-loop-helix (bHLH) domain, two Per-ARNT-Sim (PAS) domains, and a C-terminal transactivation domain (CTAD). These domains are essential for its stability, dimerization with HIF-1β, and transcriptional activity . Under normoxic conditions, HIF-1α is rapidly degraded via the ubiquitin-proteasome pathway. However, under hypoxic conditions, HIF-1α is stabilized, translocates to the nucleus, dimerizes with HIF-1β, and activates the transcription of various genes involved in angiogenesis, metabolism, and cell survival .
HIF-1α is overexpressed in many human cancers and is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia . Additionally, HIF-1α plays a role in other pathophysiologies, including chronic obstructive pulmonary disease (COPD) and sepsis .
The development of HIF-1α inhibitors, including human recombinant versions, aims to target the dysregulated HIF-1α pathway in various diseases. These inhibitors can potentially suppress tumor growth and metastasis by inhibiting HIF-1α’s ability to activate hypoxia-responsive genes. The therapeutic potential of HIF-1α inhibitors is being explored in preclinical and clinical studies for cancer and other hypoxia-related diseases .
HIF-1α inhibitors work by preventing the stabilization and activity of HIF-1α under hypoxic conditions. This can be achieved through various mechanisms, such as promoting the degradation of HIF-1α, inhibiting its dimerization with HIF-1β, or blocking its transcriptional activity. By targeting HIF-1α, these inhibitors aim to disrupt the hypoxia-induced signaling pathways that contribute to disease progression .
