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Báo cáo khoa học: Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation

To sustain life mammals have an absolute and continual requirement for oxygen, which is necessary to produce energy for normal cell survival and growth. Hence, main-tainingoxygen homeostasis is a critical requirement and mammals have evolved a wide range of cellular and phy-siological responses to adapt to changes in oxygen avail-ability. In the past few years it has become evident that the transcriptional protein complex hypoxia-inducible factor (HIF) is a key regulator of these processes. | Eur. J. Biochem. 270 781-790 2003 FEBS 2003 doi 10.1046 j.1432-1033.2003.03445.x REVIEW ARTICLE Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation David Lando1 Jeffrey J. Gorman2 Murray L. Whitelaw1 and Daniel J. Peet1 1 Department of Molecular BioSciences Biochemistry and the Centre for Molecular Genetics of Development University of Adelaide Australia 2CSIRO Health Sciences and Nutrition Parkville Victoria Australia To sustain life mammals have an absolute and continual requirement for oxygen which is necessary to produce energy for normal cell survival and growth. Hence main-tainingoxygen homeostasis is a critical requirement and mammals have evolved a wide range of cellular and physiological responses to adapt to changes in oxygen availability. In the past few years it has become evident that the transcriptional protein complex hypoxia-inducible factor HIF is a key regulator of these processes. In this review we will focus on the way oxygen availability regulates HIF proteins and in particular we will discuss the way oxygendependent hydroxylation of specific amino acid residues has been demonstrated to regulate HIF function at the level of both protein stability and transcriptional potency. Keywords oxygen sensing hypoxia hydroxylation transcriptional regulation hypoxia-inducible factor HIF . Introduction The development of complex cardiovascular respiratory and hemopoietic systems in mammals provides a means to efficiently capture and deliver oxygen O2 from the environment to every cell of the body. While a sufficient supply of oxygen is essential for energy production too much oxygen in the form of free radicals i.e. superoxide OH- can be detrimental 1 . Therefore to maximize oxygen use as well as at the same time minimize the impact of oxygen free radicals cells have developed mechanisms to maintain oxygen concentrations within a narrow physiological range. To achieve this mammals regulate oxygen consumption and