DOI:10.1038/nrc2150

URLsHIF1αhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3091&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum

HIF2αhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=2034

Hypoxia-inducible factor 1α (HIF1α) is associated with the regulation of glucose metabolism in hypoxic cells; indeed, levels of HIF1α are curtailed in cells in normoxic conditions, clearly indicating that oxygen level is a regulator of this transcription factor. However, Craig Thompson, M. Celeste Simon and colleagues now show that first and foremost, HIF1α function is governed by growth factor availability.

Evidence indicates that growth factor signalling pathways, as well as oxygen levels, can stabilize HIF1α. So Thompson and colleagues asked whether HIF1α function requires growth factor signalling. They initially used interleukin 3 (IL3)-dependent mouse haemato-poietic cell lines, and showed that in hypoxic conditions in vitro, IL3 is required to enable an increased rate of glycolysis. Moreover, the absence of IL3 altered the metabolism of glu-cose in hypoxic cells, and resulted in a lack of Hif1α mRNA expression. Short hairpin RNA (shRNA) knock-down of Hif1α resulted in a complex set of effects. In the presence of IL3 and under hypoxic conditions, wild-type cells remained viable, whereas those that expressed Hif1α shRNA did not, yet both cell types survived in hypoxic conditions in the absence of IL3. So HIF1α is required for hae-matopoietic cells to survive hypoxia when growth factors are present. However, in normoxic conditions, cells that express Hif1α shRNA had increased rates of proliferation in the presence of IL3.

These effects of HIF1α on cell proliferation were verified in Hif1α-deficient T cells. Moreover, NIH3T3 cells that expressed constitutively active HIF1α showed reduced cell

proliferation in standard culture conditions compared with controls. Further analysis indicated that HIF1α expression in the pres-ence of growth factors induced anaerobic glycolysis, which has the effect of increasing glycolytic ATP production, but limiting fatty acid synthesis and so suppressing growth. Conversely, when HIF1α expres-sion is repressed, cells metabolize less glucose through the glycolytic pathway (and so make less ATP), but more glucose is used for lipid synthesis.

So, these data support the hypothesis that HIF1α is a growth-factor-dependent transcription factor that acts to direct glucose metabolism in a way that is compatible with cell survival. So why can HIF1α be oncogenic, especially as its expres-sion in haematopoietic cells limits proliferation? The authors conclude, on the basis of these and other studies, that HIF1α might only be oncogenic in cells in which HIF2α is also expressed, which is not the case in haematopoietic cells.

Nicola McCarthy

ORIGINAL RESEARCH PAPER Lum, J. J. et al. The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 16 April 2007 (doi: 10.1101/gad1529107)

M E TA B O L I S M

A subtle role for HIF1α

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | CANCER VOLUME 7 | JUNE 2007

Nature Reviews Cancer | AOP, published online 11 May 2007; doi:10.1038/nrc2050

© 2007 Nature Publishing Group