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A dialogue between the hypoxia-inducible factor and the tumor microenvironment.

Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J - Cancer Microenviron (2008)

Bottom Line: The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension.Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix.From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Signaling, Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, Nice, France.

ABSTRACT
The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

No MeSH data available.


Related in: MedlinePlus

Proline hydroxylation drives HIFα stability and asparagine hydroxylation drives HIF activity. Left panel: Under normoxic conditions, the interaction between two hydroxy-prolyls (Pro 402 and 564 for human HIF-1α on the schematic) and the VHL protein leads to the degradation of HIFα by the proteasome. Under hypoxic conditions, because of the lack of the oxygen substrate, the HIF-prolyl hydroxylase domain (PHD) proteins do not hydroxylate these two prolyl residues, leading to stabilization of HIF-1α. Right panel: In normoxia, the hydroxylation of an asparagine residue (Asn 803 for HIF-1α on the schematic) impairs interaction between the HIFα C-terminal transactivation domain (C-TAD) and its co-activator p300/CBP. Under hypoxic conditions, because of the lack of the substrate oxygen, HIF-asparagine hydroxylase (FIH) does not hydroxylate this asparagine residue, leading to increased activity of the HIFα C-TAD. Interestingly the N-TAD is not affected by asparaginyl hydroxylation. Symbols: , stimulation; , inhibition; , interaction
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Fig2: Proline hydroxylation drives HIFα stability and asparagine hydroxylation drives HIF activity. Left panel: Under normoxic conditions, the interaction between two hydroxy-prolyls (Pro 402 and 564 for human HIF-1α on the schematic) and the VHL protein leads to the degradation of HIFα by the proteasome. Under hypoxic conditions, because of the lack of the oxygen substrate, the HIF-prolyl hydroxylase domain (PHD) proteins do not hydroxylate these two prolyl residues, leading to stabilization of HIF-1α. Right panel: In normoxia, the hydroxylation of an asparagine residue (Asn 803 for HIF-1α on the schematic) impairs interaction between the HIFα C-terminal transactivation domain (C-TAD) and its co-activator p300/CBP. Under hypoxic conditions, because of the lack of the substrate oxygen, HIF-asparagine hydroxylase (FIH) does not hydroxylate this asparagine residue, leading to increased activity of the HIFα C-TAD. Interestingly the N-TAD is not affected by asparaginyl hydroxylation. Symbols: , stimulation; , inhibition; , interaction

Mentions: Three major PHD isoforms have been described and catalyze the hydroxylation of two prolyl residues of the HIFα subunit, an action that strictly depends of the pO2 [12–14]. These two residues are located in the oxygen-dependent degradation (ODD) domain of HIFα and when hydroxylated this domain shows a strong affinity for the von Hippel-Lindau (VHL) protein, a component of a E3 ubiquitin ligase complex. The consequence is poly-ubiquitination and targeting of HIFα for degradation by the proteasome (Fig. 2). Thus an increase in HIFα protein levels in hypoxia is due to the inhibition of this oxygen-dependent degradation process.Fig. 2


A dialogue between the hypoxia-inducible factor and the tumor microenvironment.

Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J - Cancer Microenviron (2008)

Proline hydroxylation drives HIFα stability and asparagine hydroxylation drives HIF activity. Left panel: Under normoxic conditions, the interaction between two hydroxy-prolyls (Pro 402 and 564 for human HIF-1α on the schematic) and the VHL protein leads to the degradation of HIFα by the proteasome. Under hypoxic conditions, because of the lack of the oxygen substrate, the HIF-prolyl hydroxylase domain (PHD) proteins do not hydroxylate these two prolyl residues, leading to stabilization of HIF-1α. Right panel: In normoxia, the hydroxylation of an asparagine residue (Asn 803 for HIF-1α on the schematic) impairs interaction between the HIFα C-terminal transactivation domain (C-TAD) and its co-activator p300/CBP. Under hypoxic conditions, because of the lack of the substrate oxygen, HIF-asparagine hydroxylase (FIH) does not hydroxylate this asparagine residue, leading to increased activity of the HIFα C-TAD. Interestingly the N-TAD is not affected by asparaginyl hydroxylation. Symbols: , stimulation; , inhibition; , interaction
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654353&req=5

Fig2: Proline hydroxylation drives HIFα stability and asparagine hydroxylation drives HIF activity. Left panel: Under normoxic conditions, the interaction between two hydroxy-prolyls (Pro 402 and 564 for human HIF-1α on the schematic) and the VHL protein leads to the degradation of HIFα by the proteasome. Under hypoxic conditions, because of the lack of the oxygen substrate, the HIF-prolyl hydroxylase domain (PHD) proteins do not hydroxylate these two prolyl residues, leading to stabilization of HIF-1α. Right panel: In normoxia, the hydroxylation of an asparagine residue (Asn 803 for HIF-1α on the schematic) impairs interaction between the HIFα C-terminal transactivation domain (C-TAD) and its co-activator p300/CBP. Under hypoxic conditions, because of the lack of the substrate oxygen, HIF-asparagine hydroxylase (FIH) does not hydroxylate this asparagine residue, leading to increased activity of the HIFα C-TAD. Interestingly the N-TAD is not affected by asparaginyl hydroxylation. Symbols: , stimulation; , inhibition; , interaction
Mentions: Three major PHD isoforms have been described and catalyze the hydroxylation of two prolyl residues of the HIFα subunit, an action that strictly depends of the pO2 [12–14]. These two residues are located in the oxygen-dependent degradation (ODD) domain of HIFα and when hydroxylated this domain shows a strong affinity for the von Hippel-Lindau (VHL) protein, a component of a E3 ubiquitin ligase complex. The consequence is poly-ubiquitination and targeting of HIFα for degradation by the proteasome (Fig. 2). Thus an increase in HIFα protein levels in hypoxia is due to the inhibition of this oxygen-dependent degradation process.Fig. 2

Bottom Line: The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension.Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix.From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Signaling, Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, Nice, France.

ABSTRACT
The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

No MeSH data available.


Related in: MedlinePlus