HIF-1alpha

1H2K, 1H2L, 1H2M, 1L3E, 1L8C, 1LM8, 1LQB, 2ILM, 3HQR, 3HQU, 4AJY, 4H6J309115251ENSG00000100644ENSMUSG00000021109Q16665Q61221NM_181054NM_001243084NM_001530NM_010431NM_001313919NM_001313920NP_001230013NP_001521NP_851397NP_001521.1NP_001300848NP_001300849NP_034561Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. It is a basic helix-loop-helix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. The dysregulation and overexpression of HIF1A by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion. Two other alternative transcripts encoding different isoforms have been identified.1h2k: FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH HIF-1 ALPHA FRAGMENT PEPTIDE1h2l: FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH HIF-1 ALPHA FRAGMENT PEPTIDE1h2m: FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH HIF-1 ALPHA FRAGMENT PEPTIDE1l3e: NMR Structures of the HIF-1alpha CTAD/p300 CH1 Complex1l8c: STRUCTURAL BASIS FOR HIF-1ALPHA/CBP RECOGNITION IN THE CELLULAR HYPOXIC RESPONSE1lqb: Crystal structure of a hydroxylated HIF-1 alpha peptide bound to the pVHL/elongin-C/elongin-B complex Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. It is a basic helix-loop-helix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. The dysregulation and overexpression of HIF1A by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion. Two other alternative transcripts encoding different isoforms have been identified. HIF1 is a heterodimeric basic helix-loop-helix structure that is composed of HIF1A, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit. HIF1A contains a basic helix-loop-helix domain near the C-terminal, followed by two distinct PAS (PER-ARNT-SIM) domains, and a PAC (PAS-associated C-terminal) domain. The HIF1A polypeptide also contains a nuclear localization signal motif, two transactivating domains CTAD and NTAD, and an intervening inhibitory domain (ID) that can repress the transcriptional activities of CTAD and NTAD. There are a total of three HIF1A isoforms formed by alternative splicing, however isoform1 has been chosen as the canonical structure, and is the most extensively studied isoform in structure and function. The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1). HIF1A expression level is dependent on its GC-rich promoter activation. In most cells, HIF1A gene is constitutively expressed in low levels under normoxic conditions, however, under hypoxia, HIF1A transcription is often significantly upregulated. Typically, oxygen-independent pathway regulates protein expression, and oxygen-dependent pathway regulates degradation. In hypoxia-independent ways, HIF1A expression may be upregulated through a redox-sensitive mechanism. The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals. HIF1A activity is regulated by a host of post-translational modifications: hydroxylation, acetylation, and phosphorylation. HIF-1 is known to induce transcription of more than 60 genes, including VEGF and erythropoietin that are involved in biological processes such as angiogenesis and erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions. HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism. In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription. HIF1A stability, subcellular localization, as well as transcriptional activity are especially affected by oxygen level. The alpha subunit forms a heterodimer with the beta subunit. Under normoxic conditions, VHL-mediated ubiquitin protease pathway rapidly degrades HIF1a; however, under hypoxia, HIF1A protein degradation is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes Enzymes prolyl hydroxylase (PHD) and HIF prolyl hydroxylase (HPH) are involved in specific post-translational modification of HIF1A proline residues (P402 and P564 within the ODD domain), which allows for VHL association with HIF1A. The enzymatic activity of oxygen sensor dioxygenase PHD is dependent on oxygen level as it requires oxygen as one of its main substrates to transfer to the proline residue of HIF1A. The hydroxylated proline residue of HIF1A is then recognized and buried in the hydrophobic core of von Hippel-Lindau tumor suppressor protein (VHL), which itself is part of a ubiquitin ligase enzyme. The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia. Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation. In normal circumstances after injury HIF1A is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF1A via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of HIF1A results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF1A can either turn off, or turn on the key processes of mammalian regeneration. One such regenerative process in which HIF1A is involved is peripheral nerve regeneration. Following axon injury, HIF1A activates VEGFA to promote regeneration and functional recovery. HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner. In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase. PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as desferrioxamine (DFO) have proven successful in HIF1A stabilization. HBO (Hyperbaric oxygen therapy) and HIF1A imitators such as cobalt chloride have also been successfully utilized. Factors increasing HIF1A Factors decreasing HIF1A