HIF-1 alpha

HIF-1 alpha contains 1 basic helix-loop-helix (bHLH) domain, 1 PAC (PAS-associated C-terminal) domain and 2 PAS (PER-ARNT-SIM) domains. It is one of the two subunits of Hypoxia-inducible factor-1 (HIF1). HIF1 is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. HIF1 is a heterodimer composed of an alpha subunit and a beta subunit. The beta subunit has been identified as the aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-1 alpha is expressed in most tissues with highest levels in kidney and heart. It is overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. HIF-1 alpha functions as a master transcriptional regulator of the adaptive response to hypoxia.

HIF-1 alpha Related Areas

Signal Transduction>>Transcription Factor & Regulator>>HIF-1 alpha/HIF1A

HIF-1 alpha Alternative Names

HIF-1 alpha, HIF1A, HIF-1alpha, HIF-1-alpha, HIF1, HIF1-ALPHA, MOP1, PASD8, bHLHe78 [Homo sapiens]

HIF-1 alpha, Hif1a, HIF1alpha, HIF-1-alpha, HIF1-alpha, AA959795, MOP1, bHLHe78 [Mus musculus]

Summaries for HIF-1 alpha

Entrez Gene summary for HIF1A:

HIF1A encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for HIF-1 alpha.

OMIM - description for HIF-1 alpha:

Hypoxia-inducible factor-1 (HIF1) is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. HIF1 is a heterodimer composed of a 120-kD HIF1-alpha subunit complexed with a 91- to 94-kD HIF1-beta subunit

Wikipedia summary for HIF-1 alpha:

Hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor), also known as HIF-1 alpha, is a protein that in humans is encoded by the HIF1A gene. Two alternative transcripts encoding different isoforms have been identified.

Human HIF-1 alpha Protein General Information

 

• Protein names: Hypoxia-inducible factor 1-alpha, Short name=HIF-1-alpha
• Sequence length: 826 AA.
• Domain: HIF-1 alpha contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID)
• Sequence similarities: Contains 1 basic helix-loop-helix (bHLH) domain. Contains 1 PAC (PAS-associated C-terminal) domain. Contains 2 PAS (PER-ARNT-SIM) domains.
• Post-translational modification: In normoxia, HIF-1 alpha is hydroxylated on Pro-402 and Pro-577 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD1 and EGLN2/PHD2. EGLN3/PHD3 has also been shown to hydroxylate Pro-577. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization By similarity. In normoxia, is hydroxylated on Asn-813 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol By similarity.
• Subunit structure: Interacts with the HIF-1 alpha beta/ARNT subunit; heterodimerization is required for DNA binding. Interacts with Interacts with NCOA1, NCOA2, APEX and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF-1 alpha proteasomal degradation. During hypoxia, sumoylated HIF-1 alpha also binds VHL; the interaction promotes the ubiquitination of HIF-1 alpha. Interacts with SENP1; the interaction desumoylates HIF-1 alpha resulting in stabilization and activation of transcription. Interacts (Via the ODD domain) with ARD1A; the interaction appears not to acetylate HIF-1 alpha nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF-1 alpha sumoylation. Interacts with RORA (via the DNA binding domain); the interaction enhances HIF-1 alpha transcription under hypoxia through increasing protein stability. Interaction with PSMA7 inhibits the transactivation activity of HIF-1 alpha under both normoxic and hypoxia-mimicking conditions. Interacts with USP20. Interacts with GNB2L1/RACK1; promotes HIF-1 alpha ubiquitination and proteasome-mediated degradation. Interacts with EP300 (via TAZ-type 1 domain); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domain) By similarity. Interacts with COPS5; the interaction increases the transcriptional activity of HIF-1 alpha through increased stability. Interacts with TSGA10.
• Subcellular location: Cytoplasm. Nucleus. Note: Cytoplasmic in normoxia, nuclear translocation in response to hypoxia. Colocalizes with SUMO1 in the nucleus, under hypoxia By similarity.
• Tissue specificity: Ubiquitous.
• Induction: Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia. Repressed by HIPK2.

General information above from UniProt

Function for HIF-1 alpha Protein

UniProtKB:

HIF-1 alpha functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions HIF-1 alpha activates the transcription of over 40 genes, including, erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 alpha plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. HIF-1 alpha binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP.

Genatlas:

• HIF-1 alpha is involved (essential) in cardiovascular development and systemic O2 homeostasis
• HIF-1 alpha is essential for the regulation of glycolytic capacity in myeloid cells, has a role in regulation of survival and function in the inflammatory microenvironmen
• HIF-1 alpha is controlled through stability regulation of its alpha subunit, which is expressed under hypoxia but degraded under normoxia
• HIF-1 alpha regulats the expression of TWIST1 by binding directly to the hypoxia-response element (HRE) in the TWIST1 proximal promoter
• HIF-1 alpha promotes glycogen accumulation through regulating PPP1R3C expression under hypoxia, which revealed a novel metabolic adaptation of cells to hypoxia)
• HIF-1 alpha may be directly or indirectly required for normal development of the retinal vasculature, especially of the intermediate plexus

Homology for human HIF-1 alpha

• ortholog to Hif1a, Rattus norvegicus
• ortholog to Hif1a, Mus musculus
• ortholog to HIF1A, Pan troglodytes