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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

Schematic of the structure of the three HIFα and the two HIFβ isoforms. NLS, nuclear localization signal; bHLH, basic helix-loop helix-domain; PAS, per arnt sim domain subdivided into PAS A and PAS B; ODD, oxygen-dependent degradation domain; TAD, transactivation domain. HIF-1α and HIF-2α have two distinct TAD, in the C- (C-TAD) and N- (N-TAD) terminal domains. The PAS and bHLH domains are dedicated to dimerization and recognition of target DNA sequences
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Fig1: Schematic of the structure of the three HIFα and the two HIFβ isoforms. NLS, nuclear localization signal; bHLH, basic helix-loop helix-domain; PAS, per arnt sim domain subdivided into PAS A and PAS B; ODD, oxygen-dependent degradation domain; TAD, transactivation domain. HIF-1α and HIF-2α have two distinct TAD, in the C- (C-TAD) and N- (N-TAD) terminal domains. The PAS and bHLH domains are dedicated to dimerization and recognition of target DNA sequences

Mentions: Hypoxia is a condition encountered in both physiological (embryonic development) and pathophysiological (ischemia diseases, diabetes, atherosclerosis, Alzheimer’s disease, chronic obstructive pulmonary disease, inflammatory disorders, pre-eclampsia, psoriasis and cancer) situations. Cells exposed to a hypoxic stress must rapidly adapt, otherwise an imbalance in their energy supply/consumption ratio ensues. Hypoxia activates a global signaling network centered on the key element, the hypoxia-inducible factor (HIF) [5, 7, 8]. Thus low oxygen tension is the prototypic regulator of HIF. This factor transcriptionally activates a panel of microenvironmental adaptation genes that contribute to rapid cell survival [5, 9, 10]. In addition to survival, the HIF signaling pathway confers on cancer cells an arsenal that allows them to become more aggressive. So, how is the transcriptional machinery activated in response to variations in the pO2? HIF is a heterodimer composed of an O2 regulated alpha subunit and a constitutively expressed beta subunit (Fig. 1). Several HIF alpha and beta isoforms have been described in mammals, where HIF-1α, HIF-2α and HIF-1β are the best characterized to date.Fig. 1


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

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

Schematic of the structure of the three HIFα and the two HIFβ isoforms. NLS, nuclear localization signal; bHLH, basic helix-loop helix-domain; PAS, per arnt sim domain subdivided into PAS A and PAS B; ODD, oxygen-dependent degradation domain; TAD, transactivation domain. HIF-1α and HIF-2α have two distinct TAD, in the C- (C-TAD) and N- (N-TAD) terminal domains. The PAS and bHLH domains are dedicated to dimerization and recognition of target DNA sequences
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Schematic of the structure of the three HIFα and the two HIFβ isoforms. NLS, nuclear localization signal; bHLH, basic helix-loop helix-domain; PAS, per arnt sim domain subdivided into PAS A and PAS B; ODD, oxygen-dependent degradation domain; TAD, transactivation domain. HIF-1α and HIF-2α have two distinct TAD, in the C- (C-TAD) and N- (N-TAD) terminal domains. The PAS and bHLH domains are dedicated to dimerization and recognition of target DNA sequences
Mentions: Hypoxia is a condition encountered in both physiological (embryonic development) and pathophysiological (ischemia diseases, diabetes, atherosclerosis, Alzheimer’s disease, chronic obstructive pulmonary disease, inflammatory disorders, pre-eclampsia, psoriasis and cancer) situations. Cells exposed to a hypoxic stress must rapidly adapt, otherwise an imbalance in their energy supply/consumption ratio ensues. Hypoxia activates a global signaling network centered on the key element, the hypoxia-inducible factor (HIF) [5, 7, 8]. Thus low oxygen tension is the prototypic regulator of HIF. This factor transcriptionally activates a panel of microenvironmental adaptation genes that contribute to rapid cell survival [5, 9, 10]. In addition to survival, the HIF signaling pathway confers on cancer cells an arsenal that allows them to become more aggressive. So, how is the transcriptional machinery activated in response to variations in the pO2? HIF is a heterodimer composed of an O2 regulated alpha subunit and a constitutively expressed beta subunit (Fig. 1). Several HIF alpha and beta isoforms have been described in mammals, where HIF-1α, HIF-2α and HIF-1β are the best characterized to date.Fig. 1

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