Limits...
Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia.

Ziello JE, Jovin IS, Huang Y - Yale J Biol Med (2007)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vascular Biology and Transplantation Program, Yale University, New Haven, Connecticut 06520, USA.

ABSTRACT
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. 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. 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. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. 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. 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. 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. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia.

Show MeSH

Related in: MedlinePlus

The hypoxia-inducible factor (HIF)-1 pathway. The HIF-1α gene is transcribed in the nucleus with the help of specificity protein (Sp) 1, P300, and HIF-1β. Once translated in the cytoplasm, the HIF-1α protein can either become hydroxylated and ubiquinated, in which case it will be degraded by proteasomes (under normal oxygen conditions). In the setting of hypoxia, it can re-enter the nucleus and form a transcription complex with the HIF-1β subunit. If successfully stabilized with the latter subunit, the final complex ultimately will function to regulate target genes such as vascular endothelial growth factor and cathepsin D.  Possible therapeutic intervention points are: the hydroxylation that leads to degradation of HIF-1α, the binding of HIF-1α to its coactivators, and the modulation of HIF-1α activity. Additionally, gene therapy approaches have been used to induce the overexpression of HIF or the disruption of the HIF pathway with antisense oligonucleotides. Abbreviations: PHD: proline-hydroxylase domain containing molecules; Ub: ubiquitin; VHL: von Hippel-Lindau protein.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2140184&req=5

Figure 2: The hypoxia-inducible factor (HIF)-1 pathway. The HIF-1α gene is transcribed in the nucleus with the help of specificity protein (Sp) 1, P300, and HIF-1β. Once translated in the cytoplasm, the HIF-1α protein can either become hydroxylated and ubiquinated, in which case it will be degraded by proteasomes (under normal oxygen conditions). In the setting of hypoxia, it can re-enter the nucleus and form a transcription complex with the HIF-1β subunit. If successfully stabilized with the latter subunit, the final complex ultimately will function to regulate target genes such as vascular endothelial growth factor and cathepsin D. Possible therapeutic intervention points are: the hydroxylation that leads to degradation of HIF-1α, the binding of HIF-1α to its coactivators, and the modulation of HIF-1α activity. Additionally, gene therapy approaches have been used to induce the overexpression of HIF or the disruption of the HIF pathway with antisense oligonucleotides. Abbreviations: PHD: proline-hydroxylase domain containing molecules; Ub: ubiquitin; VHL: von Hippel-Lindau protein.

Mentions: However, in hypoxic conditions, HIF-1 protein is stable and active as hydroxylases, VHL proteins, and FIH are all inhibited by a lack of oxygen. Then HIF-1 is able to interact with its co-activators and can dimerize with its constitutively expressed β-subunit. Once stabilized, the HIF-1 protein can bind to the regulatory regions of its target genes, inducing their expression [7,10,27] [Figure 2].


Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia.

Ziello JE, Jovin IS, Huang Y - Yale J Biol Med (2007)

The hypoxia-inducible factor (HIF)-1 pathway. The HIF-1α gene is transcribed in the nucleus with the help of specificity protein (Sp) 1, P300, and HIF-1β. Once translated in the cytoplasm, the HIF-1α protein can either become hydroxylated and ubiquinated, in which case it will be degraded by proteasomes (under normal oxygen conditions). In the setting of hypoxia, it can re-enter the nucleus and form a transcription complex with the HIF-1β subunit. If successfully stabilized with the latter subunit, the final complex ultimately will function to regulate target genes such as vascular endothelial growth factor and cathepsin D.  Possible therapeutic intervention points are: the hydroxylation that leads to degradation of HIF-1α, the binding of HIF-1α to its coactivators, and the modulation of HIF-1α activity. Additionally, gene therapy approaches have been used to induce the overexpression of HIF or the disruption of the HIF pathway with antisense oligonucleotides. Abbreviations: PHD: proline-hydroxylase domain containing molecules; Ub: ubiquitin; VHL: von Hippel-Lindau protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2140184&req=5

Figure 2: The hypoxia-inducible factor (HIF)-1 pathway. The HIF-1α gene is transcribed in the nucleus with the help of specificity protein (Sp) 1, P300, and HIF-1β. Once translated in the cytoplasm, the HIF-1α protein can either become hydroxylated and ubiquinated, in which case it will be degraded by proteasomes (under normal oxygen conditions). In the setting of hypoxia, it can re-enter the nucleus and form a transcription complex with the HIF-1β subunit. If successfully stabilized with the latter subunit, the final complex ultimately will function to regulate target genes such as vascular endothelial growth factor and cathepsin D. Possible therapeutic intervention points are: the hydroxylation that leads to degradation of HIF-1α, the binding of HIF-1α to its coactivators, and the modulation of HIF-1α activity. Additionally, gene therapy approaches have been used to induce the overexpression of HIF or the disruption of the HIF pathway with antisense oligonucleotides. Abbreviations: PHD: proline-hydroxylase domain containing molecules; Ub: ubiquitin; VHL: von Hippel-Lindau protein.
Mentions: However, in hypoxic conditions, HIF-1 protein is stable and active as hydroxylases, VHL proteins, and FIH are all inhibited by a lack of oxygen. Then HIF-1 is able to interact with its co-activators and can dimerize with its constitutively expressed β-subunit. Once stabilized, the HIF-1 protein can bind to the regulatory regions of its target genes, inducing their expression [7,10,27] [Figure 2].

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vascular Biology and Transplantation Program, Yale University, New Haven, Connecticut 06520, USA.

ABSTRACT
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. 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. 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. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. 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. 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. 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. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia.

Show MeSH
Related in: MedlinePlus