Signal transduction to hypoxia-inducible factor 1

doi:10.1016/S0006-2952(02)01168-1

Biochemical Pharmacology

Volume 64, Issues 5–6, September 2002, Pages 993-998

https://doi.org/10.1016/S0006-2952(02)01168-1 Get rights and content

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that functions as a master regulator of O₂ homeostasis. HIF-1 target genes encode proteins that increase O₂ delivery and mediate adaptive responses to O₂ deprivation. HIF-1 activity is regulated by the cellular O₂ concentration and by the major growth factor-stimulated signal transduction pathways. In human cancer cells, both intratumoral hypoxia and genetic alterations affecting signal transduction pathways lead to increased HIF-1 activity, which promotes angiogenesis, metabolic adaptation, and other critical aspects of tumor progression.

Section snippets

Hypoxia signal transduction

HIF-1α is subject to rapid ubiquitination and proteasomal degradation under non-hypoxic conditions [2], [3], [4] and this process is inhibited under hypoxic conditions [5], resulting in an exponential increase in HIF-1α levels as the cellular O₂ concentration is decreased (Fig. 1), both in cultured cells [6] and in vivo[7]. The molecular basis for this regulation is the O₂-dependent hydroxylation of proline residues 402 and 564 in HIF-1α by any one of three enzymes in mammals that have been

Signaling of the PI3K-AKT-FRAP pathway to HIF-1α

Stimulation of cells with a variety of growth factors and cytokines, including epidermal growth factor (EGF), fibroblast growth factor 2, heregulin, insulin, insulin-like growth factor 1 and 2, and interleukin-1β induce the expression of HIF-1α protein, HIF-1 DNA-binding activity, and HIF-1 target gene expression under non-hypoxic conditions [14], [15], [16], [17]. Binding of these ligands to their cognate receptor tyrosine kinases activates a variety of signal transduction pathways, including

Signaling of the MAP kinase pathway to HIF-1α

Receptor tyrosine kinase activity also leads to signaling via the ERK (p42 and p44) and p38 MAP kinase pathways. HIF-1α is phosphorylated by p42, p44, p38α, and p38γ in vitro[21], [22], although the precise residues have not been defined. In CCL39 cells, RAF-1 overexpression is associated with phosphorylation of p42/p44 and a mobility shift of HIF-1α that is blocked by treatment with PD098059, an inhibitor of the MAP kinase kinase MEK-1. RAF-1 activity is associated with increased

Implications for cancer biology and therapy

Intratumoral hypoxia and genetic alterations that dysregulate signal transduction pathways result in the dramatic overexpression of HIF-1α in the majority of human cancers analyzed by immunohistochemistry [26], [27]. As described above, these tumor-specific physiologic and genetic alterations stimulate HIF-1α protein synthesis or stability as well as transactivation domain function (Fig. 1), although the latter cannot be assayed by immunohistochemistry. HIF-1α overexpression is associated with

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Signal transduction to hypoxia-inducible factor 1

Abstract

Section snippets

Hypoxia signal transduction

Signaling of the PI3K-AKT-FRAP pathway to HIF-1α

Signaling of the MAP kinase pathway to HIF-1α

Implications for cancer biology and therapy

J. Biol. Chem.

J. Biol. Chem.

Cell

Blood

J. Biol. Chem.

J. Biol. Chem.

Blood

Am. J. Pathol.

Trends Mol. Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension

Proc. Natl. Acad. Sci. U.S.A.

Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway

Proc. Natl. Acad. Sci. U.S.A.

HIF-1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations

Proc. Natl. Acad. Sci. U.S.A.

Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension

Am. J. Physiol.

Temporal, spatial and oxygen-regulated expression of hypoxia-inducible factor 1 in the lung

Am. J. Physiol.

A conserved family of prolyl-4-hydroxylases that modify HIF

Science

HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing

Science

Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation

Science

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

Nature

FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity

Genes Dev.

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension

Regulation of hypoxia-inducible factor 1α is mediated by an O₂-dependent degradation domain via the ubiquitin-proteasome pathway

Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O₂ tension

HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O₂ sensing

Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O₂-regulated prolyl hydroxylation