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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.

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Related in: MedlinePlus

The structure of the HIF-1α and HIF-1β genes. 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 carboxy-terminal transactivation domains of these genes serve as regulatory and transactivation regions. Transcriptional activators CBP and p300 bind to the TAD-C region of the HIF-1α gene.  Also depicted on the diagram of HIF-1α gene is the inhibitory domain, an important regulatory region.
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Figure 1: The structure of the HIF-1α and HIF-1β genes. 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 carboxy-terminal transactivation domains of these genes serve as regulatory and transactivation regions. Transcriptional activators CBP and p300 bind to the TAD-C region of the HIF-1α gene. Also depicted on the diagram of HIF-1α gene is the inhibitory domain, an important regulatory region.

Mentions: HIF-1 is a heterodimeric transcription factor consisting of a constitutively expressed β-subunit and an oxygen-regulated α-subunit. The HIF-1α and HIF-1β proteins both contain basic helix-loop-helix motifs that bind DNA and cause subunit dimerization [7,8,9]. Both subunits also have a Per-ARNT-Sim (PAS) domain, with similar functions. In the α-subunit, there is an oxygen-dependent degradation (ODD) domain, which is hydroxylated by proline-hydroxylase-2 (PHD-2), rendering the α-subunit vulnerable to proteasomal degradation under normoxic cellular conditions [10]. The structure of HIF-1α and HIF-1β is depicted in Figure 1.


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 structure of the HIF-1α and HIF-1β genes. 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 carboxy-terminal transactivation domains of these genes serve as regulatory and transactivation regions. Transcriptional activators CBP and p300 bind to the TAD-C region of the HIF-1α gene.  Also depicted on the diagram of HIF-1α gene is the inhibitory domain, an important regulatory region.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The structure of the HIF-1α and HIF-1β genes. 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 carboxy-terminal transactivation domains of these genes serve as regulatory and transactivation regions. Transcriptional activators CBP and p300 bind to the TAD-C region of the HIF-1α gene. Also depicted on the diagram of HIF-1α gene is the inhibitory domain, an important regulatory region.
Mentions: HIF-1 is a heterodimeric transcription factor consisting of a constitutively expressed β-subunit and an oxygen-regulated α-subunit. The HIF-1α and HIF-1β proteins both contain basic helix-loop-helix motifs that bind DNA and cause subunit dimerization [7,8,9]. Both subunits also have a Per-ARNT-Sim (PAS) domain, with similar functions. In the α-subunit, there is an oxygen-dependent degradation (ODD) domain, which is hydroxylated by proline-hydroxylase-2 (PHD-2), rendering the α-subunit vulnerable to proteasomal degradation under normoxic cellular conditions [10]. The structure of HIF-1α and HIF-1β is depicted in Figure 1.

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