Signal transduction to hypoxia-inducible factor 1
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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