Abstract
Hypoxia‚ or decreases in oxygen availability‚ results in the activation of a number of different responses at both the whole organism and the cellular level. These responses include drastic changes in gene expression, which allow the organism (or cell) to cope efficiently with the stresses associated with the hypoxic insult. A major breakthrough in the understanding of the cellular response to hypoxia was the discovery of a hypoxia sensitive family of transcription factors known as the hypoxia inducible factors (HIFs). The hypoxia response mounted by the HIFs promotes cell survival and energy conservation. As such, this response has to deal with important cellular process such as cell division. In this review, the integration of oxygen sensing with the cell cycle will be discussed. HIFs, as well as other components of the hypoxia pathway, can influence cell cycle progression. The role of HIF and the cell molecular oxygen sensors in the control of the cell cycle will be reviewed.
Highlights
Hypoxia‚ or decreases in oxygen concentration‚ results in the activation of a number of different responses both at the cellular and whole organism level [1]
In hypoxia, when cells are exposed to reduced levels of oxygen, prolyl hydroxylases (PHDs) activity is reduced leading to HIFα stabilization and dimerization with its transcriptional partner HIF1β
In addition to regulation of HIFα turnover by the PHDs, fine-tuning of hypoxia inducible factors (HIFs)-dependent transcription is achieved through an asparagine hydroxylation within the C-terminal transactivation domain (CTAD) of HIF1α and HIF2α, mediated by a ubiquitously expressed Factor Inhibiting HIF (FIH) protein [26]
Summary
Hypoxia‚ or decreases in oxygen concentration‚ results in the activation of a number of different responses both at the cellular and whole organism level [1]. In hypoxia, when cells are exposed to reduced levels of oxygen, PHD activity is reduced leading to HIFα stabilization and dimerization with its transcriptional partner HIF1β. In addition to regulation of HIFα turnover by the PHDs, fine-tuning of HIF-dependent transcription is achieved through an asparagine hydroxylation within the C-terminal transactivation domain (CTAD) of HIF1α and HIF2α, mediated by a ubiquitously expressed Factor Inhibiting HIF (FIH) protein [26]. Asparagine hydroxylation within the CTAD prevents HIF interaction with its transcriptional co-activators p300 and/CREB– cAMP-response element binding protein (CBP) and as a consequence prevents full target gene activation [27]. In contrast to the PHDs, FIH is much less sensitive to oxygen levels and some studies have suggested that FIH acts as more of a redox sensor within the cell, as it is strongly inhibited by peroxide [28]. Solid tumours are extremely hypoxic and cells in these regions have been found to be resistant to chemo and radiotherapy [35]
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