Negative and positive regulation of HIF-1: a complex network.

Hypoxia inducible factor-1 (HIF-1) is as a key transcriptional mediator of the hypoxic response in eukaryotic cells, regulating the expression of a myriad of genes involved in oxygen transport, glucose uptake and glycolysis and angiogenesis. Deregulation of HIF-1 activity occurs in many human cancers, usually at the level of the HIF-1alpha subunit. HIF-1 is regulated by a variety of mechanisms including transcription, translation post-translational modification, protein-protein interaction and degradation.

Growth factor-mediated induction of HDM2 positively regulates hypoxia-inducible factor 1alpha expression.

The hypoxia-inducible factor 1 (HIF-1) transcriptional complex is regulated by cellular oxygen levels and growth factors. The phosphoinosotide 3-kinase (PI-3K)-Akt/protein kinase B (PKB) pathway has been shown to regulate HIF-1 activity in response to oncogenic signals and growth factors. We assessed whether the HDM2 oncoprotein, a direct target of Akt/PKB, could regulate HIF-1alpha expression and HIF-1 activity under normoxic conditions.

Hypoxia-inducible factor-1 and oncogenic signalling.

An understanding of underlying mechanisms involved in the activation of HIF-1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF-1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, resulting in their ability to form vascular tumours, which are aggressive and metastatic.