HIF1A

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric is_associated_with::transcription factor hypoxia-inducible factor 1 (is_associated_with::HIF-1) that is encoded by the HIF1A is_associated_with::gene. It is a is_associated_with::basic helix-loop-helix is_associated_with::PAS domain containing is_associated_with::protein, and is considered as the master is_associated_with::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 is_associated_with::vascularization and is_associated_with::angiogenesis, energy is_associated_with::metabolism, cell survival, and tumor invasion. Two other alternative transcripts encoding different is_associated_with::isoforms have been identified.

Structure
HIF1 is a is_associated_with::heterodimeric is_associated_with::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 is_associated_with::C-terminal, followed by two distinct PAS (PER-ARNT-SIM) domains, and a is_associated_with::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.

Gene and expression
The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1). HIF1A expression level is depedent 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 is_associated_with::redox-sensitive mechanism.

Function
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 is_associated_with::post-translational modifications: is_associated_with::hydroxylation, is_associated_with::acetylation, and is_associated_with::phosphorylation. HIF-1 is known to induce transcription of more than 60 genes, including is_associated_with::VEGF and is_associated_with::erythropoietin that are involved in biological processes such as is_associated_with::angiogenesis and is_associated_with::erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions. HIF-1 also induces transcription of genes involved in is_associated_with::cell proliferation and survival, as well as glucose and iron is_associated_with::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 activityare especially affected by oxygen level. HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism. The alpha subunit forms a heterodimer with the beta subunit. Under is_associated_with::normoxic conditions, pVHL-mediated ubiquitin protease pathway rapidly degrades HIF1a; however, under hypoxia, HIF1A is_associated_with::protein degradation is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes Enzymes is_associated_with::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 pVHL association with HIF1A. The enzymatic activity of oxygen sensor is_associated_with::dioxygenase PHD is dependent on oxygen level as it requires oxygen as one of its main substrates to transfer to the is_associated_with::proline residue of HIF1A. The hydroxylated proline residue of HIF1A is then recognized and buried in the is_associated_with::hydrophobic core of is_associated_with::von Hippel-Lindau is_associated_with::tumor suppressor protein (pVHL), which itself is part of a is_associated_with::ubiquitin ligase is_associated_with::enzyme. The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia.

Repair and regeneration
In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF1Avia 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.

Regulation
HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an is_associated_with::NF-κB-dependent manner. In addition, the coordinated activity of the is_associated_with::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 is_associated_with::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


 * Modulator of Degradation:
 * Oxygen-Dependent:
 * EPF UCP (degrades pHVL)
 * VDU2  (de-ubiquitinates HIF1A)
 * SUMOylation (via RSUME)
 * DeSUMOylation ( via is_associated_with::SENP1)
 * Oxygen-independent:
 * Calcineurin A ( Ca2+-dependent via RACK1)
 * Modulators of translation:
 * RNA-binding proteins, PTB, and HuR
 * is_associated_with::PtdIns3K and MAPK pathways
 * IRES-mediated translation
 * calcium signaling
 * is_associated_with::miRNAs

Factors decreasing HIF1A


 * Modulator of Degradation:
 * Oxygen-Dependent:
 * PHD, pVHL, is_associated_with::OS-9 and SSAT2
 * SUMOylation
 * Oxygen-independent
 * is_associated_with::RACK1 and SSAT1
 * GSK3β
 * is_associated_with::FOXO4
 * Modulators of translation:
 * Calcium signaling
 * miRNAs

Role in cancer
HIF-1 is overexpressed in many human cancers. HIF-1 overexpression is heavily implicated in promoting tumor growth and metastasis through its role role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia. Hypoxia promotes apoptosis in both normal and tumor cells. However, hypoxic conditions in is_associated_with::tumor microenvironment especially, along with accumulation of genetic alternations often contribute to HIF-1 overexpression.

Significant HIF-1 expression has been noted in most solid tumors studied, which include cancers of the colon, is_associated_with::breast, is_associated_with::pancreas, is_associated_with::kidneys, is_associated_with::prostate, is_associated_with::ovary, is_associated_with::brain, and is_associated_with::bladder. Clinically, elevated Hif-1a levels in a number of cancers, including is_associated_with::cervical cancer, is_associated_with::non-small-cell lung carcinoma, is_associated_with::breast cancer (LV-positive and negative), is_associated_with::oligodendroglioma, is_associated_with::oropharyngeal cancer, is_associated_with::ovarian cancer, is_associated_with::endometrial cancer, is_associated_with::esophageal cancer, is_associated_with::head and neck cancer, and is_associated_with::stomach cancer, have been associated with aggressive tumor progression, and thus has been implicated as a predictive and prognostic marker for resistance to is_associated_with::radiation treatment, is_associated_with::chemotherapy, and increased mortality.

HIF1A expression may also regulate breast is_associated_with::tumor progression. Elevated HIF1A levels may be detected in early cancer development, and have been found in early is_associated_with::ductal carcinoma in situ, a pre-invasive stage in breast cancer development, and is also associated with increased is_associated_with::microvasculature density in tumor is_associated_with::lesions. Moreover, despite histologically-determined low-grade, lymph-node negative breast tumor in a subset of patients examined, detection of significant HIF1A expression was able to independently predict poor response to therapy. Similar findings have been reported in brain cancer and ovarian cancer studies as well, and suggest at regulatory role of HIF1A in initiating is_associated_with::angiogenesis through interactions with pro-angiogenic factors such as is_associated_with::VEGF. Studies of is_associated_with::glioblastoma multiforme show striking similarity between HIF1A expression pattern and that of is_associated_with::VEGF is_associated_with::gene transcription level. In addition, high-grade glioblastoma multiform tumors with high VEGF expression pattern, similar to breast cancer with HIF1A overexpression, display significant signs of tumor is_associated_with::neovascularization. This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways.

HIF1A overexpression in tumors may also occur in a hypoxia-independent pathway. In hemagioblastoma, HIF1A expression is found in most cells sampled from the well-vascularized tumor. Although in both renal carcinoma and hemagioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels. In addition to VEGF overexpression in response elevated HIF1A levels, the is_associated_with::PI3K/is_associated_with::AKT pathway is also involved in tumor growth. In prostate cancers, the commonly occurring PTEN mutation is associated with tumor progression toward aggressive stage, increased vascular density and angiogenesis.

During hypoxia, is_associated_with::tumor suppressor is_associated_with::p53 overexpression may be associated with HIF1A-dependent pathway to initiate apoptosis. Moreover, p53-independent pathway may also induce apoptosis through the is_associated_with::Bcl-2 pathway. However, overexpression of HIF1A is cancer- and individual-specific, and depends on the accompanying genetic alternations and levels of pro- and anti-apoptotic factors present. One study on epithelial ovarian cancer shows HIF1A and nonfunctional tumor suppressor is_associated_with::p53 is correlated with low levels of tumor cell apoptosis and poor prognosis. Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy. Studies of glioblastoma multiforme show striking similarity between HIF1A protein expression pattern and that of VEGF gene transcription level.

While research efforts to develop therapeutic drugs to target hypoxia-associated tumor cells have been ongoing for many years, there has not yet been any breakthrough that has shown selectivity and effectiveness at targeting HIF1A pathways to decrease tumor progression and angiogenesis. Successful therapeutic approaches in the future may also be highly case-specific to particular cancers ad individuals, and seem unlikely to be widely applicable due to the genetically is_associated_with::heterogenous nature of the many cancer types and subtypes.

Interactions
HIF1A has been shown to interact with:


 * is_associated_with::ARNTL,
 * ARNT,
 * CREBB,
 * is_associated_with::EP300,
 * is_associated_with::HIF1AN,
 * is_associated_with::Mdm2,
 * NR4A,
 * is_associated_with::P53,
 * is_associated_with::PSMA7,
 * is_associated_with::STAT3,
 * UBC,
 * VH         and
 * pVHL.