As a tumor develops and grows, a hypoxic environment is created because of the extreme energy demands of the numerous, rapidly dividing cells. ĭue to its role in hypoxia, HIF-1 plays a critical part in tumor proliferation. Recent reports show that HIF-1β is identical to the previously discovered vertebrate protein, aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-1β contains only one such analogous region, which is unnecessary for HIF-1 complex function. CREB binding protein (CBP) and p300, two transcriptional co-activators of HIF-1, interact with the carboxy-terminal transactivation domain (C-TAD) of HIF-1α.īoth activators are essential for HIF-1 transcription and are therefore targets in the effort to regulate HIF-1 expression inhibition of HIF-1α C-TAD interactions by proline hydroxylation inhibits HIF-1 gene expression, preventing normal transcription and translation. The HIF-1α subunit also contains two transactivation domains (TAD), which regulate HIF-1 target genes. Also depicted on the diagram of HIF-1α gene is the inhibitory domain, an important regulatory region. Transcriptional activators CBP and p300 bind to the TAD-C region of the HIF-1α gene. The carboxy-terminal transactivation domains of these genes serve as regulatory and transactivation regions. These genes contain a basic helix-loop-helix (bHLH) motif and Per-ARNT-Sim (PAS) domain, both of which aid in dimerization and the binding of the subunits to DNA. The structure of the HIF-1α and HIF-1β genes. Although no such human protein has been successfully regulated by scientific means, control of HIF-1 activity is increasingly feasible as details of its structure, function, and genetic pathway are elucidated. Given its prominent function, manipulation of HIF-1 activity within areas of ischemia and tumor masses has become a focus in the effort to develop noninvasive, pharmaceutical treatment options for cancer and heart disease patients. While microenvironments surrounding cancerous tumors are extremely hypoxic, proliferation of such masses often is made possible by HIF-1 activation, which leads to increased angiogenesis and, thus, an increased oxygen supply to the area. Genes such as HIF-1, whose activation is prompted by hypoxic conditions, can interact with enzymes and other transcription factors in order to control vascularization and tissue growth. Changing oxygen levels can result in activation or repression of certain homeostatic regulatory genes, allowing for the survival of tissues and cells despite fluctuating environmental conditions. Many organisms have evolved adaptive mechanisms for hypoxic conditions. Such findings indicate that in addition to genetic cues, environmental conditions such as hypoxia serve as signals in embryonic development. Although the exact mechanisms are unknown, oxygen tension is related to closure of the neural tube, mediation of apoptosis, and proper morphological development during gestation. It is integral for proper embryonic development. However, hypoxia also can play an important and beneficial role in human physiology and development. Depending on the severity, permanent damage to tissues and cells may occur. Hypoxia, or oxygen deprivation, occurs within human tissues and cells due to a variety of conditions, including disorders of the heart and lungs, anemia, and circulatory problems. Oxygen is required by the cells of most organisms to produce adequate amounts of ATP necessary for metabolic activities. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia. Gene therapy to achieve both vessel proliferation and tumor regression has been demonstrated in animal studies but requires significant improvement and modification before becoming commercially available. With a growing understanding of the HIF-1 pathway, the inhibition and stimulation of its transcriptional activity via small molecules is now an attractive goal. In contrast, as HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. It is a transcription factor for dozens of target genes HIF-1 is also essential for immunological responses and is a crucial physiological regulator of homeostasis, vascularization, and anaerobic metabolism. HIF-1 is among the primary genes involved in the homeostatic process, which can increase vascularization in hypoxic areas such as localized ischemia and tumors. Hypoxia-Inducible Factor (HIF)-1 is a dimeric protein complex that plays an integral role in the body's response to low oxygen concentrations, or hypoxia.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |