Turn me on: regulating HIF transcriptional activity

Abstract

The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

Angiogenesis and Multiple Myeloma

“…Tumor adaptation to hypoxia is mainly due to the hypoxia-inducible factor (HIF)-1, a key transcription factor that regulates angiogenesis and tumor progression in solid cancers [106][107][108][109][110][111]. HIF-1 is a heterodimeric DNA binding complex composed of two basic helix-loop-helix proteins, including the constitutively expressed HIF-1β and the hypoxia-inducible α-subunit HIF-1α [106][107][108][109].…”

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

“…It is worth noting that the activity of the HRE multimer, very elevated under basal conditions, doubled in 1833 cells transfected with HIF-1α. This overexpression of the exogenous α subunit seemed to partly reproduce the effect of TGF-1 in the regulation of COX-2 transcription, because HIF-1 activation is complex requiring translocation and phosphorylation of the α subunit, beyond stabilization, and the possible co-operation with other transcription factors and transcriptional coactivators [35].…”

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

“…[16][17][18] Tumor adaptation to hypoxia is mainly due to the hypoxia-inducible factor (HIF)-1, a key transcription factor that regulates pro-angiogenic factors, angiogenesis and tumor progression in solid tumors. [19][20][21][22][23] HIF-1 is a heterodimeric DNA binding complex highly inducible by hypoxia and is composed of two basic helix-loop-helix proteins, including the constitutive HIF-1b subunit and the hypoxiainducible a-subunit. [19][20][21] Under normoxic conditions HIF-1a has a very short half-life undergoing proteosomal degradation by oxygen-dependent hydroxylation.…”

“…[19][20][21][22][23] HIF-1 is a heterodimeric DNA binding complex highly inducible by hypoxia and is composed of two basic helix-loop-helix proteins, including the constitutive HIF-1b subunit and the hypoxiainducible a-subunit. [19][20][21] Under normoxic conditions HIF-1a has a very short half-life undergoing proteosomal degradation by oxygen-dependent hydroxylation. In contrast, under hypoxic condition, hydroxylation is suppressed and HIF-1a protein escapes proteasomal destruction and can accumulate and translocate to the nucleus.…”

“…In contrast, under hypoxic condition, hydroxylation is suppressed and HIF-1a protein escapes proteasomal destruction and can accumulate and translocate to the nucleus. [19][20][21] HIF-1a is a critical trigger and regulator of tumor associated angiogenesis. 22,23 Interestingly a critical role of HIF-1a in osteoclast formation and regulation has been shown 24,25 as well as its role in the development of osteolytic metastasis in breast cancer model.…”