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Evolutionarily conserved developmental pathways



Regulatory responses to decreased oxygen concentrations: a role for the heterodimeric bHLH-PAS transcription hypoxia-inducible factor

In mammalian systems, the heterodimeric basic helix-loop-helix (bHLH)-PAS transcription hypoxia-inducible factor (HIF) has emerged as the key regulator of responses to decreased oxygen concentrations (reviewed by Semenza, 2001; see also Kaelin, 2002; Bruick, 2003; Bracken, 2003; Bruick, 2004). A homologous system is present in Drosophila, and its activity has been characterized in vivo during development. By using transcriptional reporters in developing transgenic flies, it has been shown that hypoxia-inducible activity rises to a peak in late embryogenesis and is most pronounced in tracheal cells. The bHLH-PAS proteins Similar (Sima) and Tango (Tgo) function as HIF-alpha and HIF-ß homologs, respectively; a conserved mode of regulation for Sima by oxygen has been demonstrated. Sima protein, but not its mRNA, is upregulated in hypoxia. Time course experiments following pulsed ectopic expression demonstrate that Sima is stabilized in hypoxia and that degradation relies on a central domain encompassing amino acids 692 to 863. Continuous ectopic expression overrode Sima degradation, which remains cytoplasmic in normoxia, and translocates to the nucleus only in hypoxia, revealing a second oxygen-regulated activation step. Abrogation of the Drosophila Egl-9 prolyl hydroxylase homolog, CG1114, causes both stabilization and nuclear localization of Sima, indicating a central involvement in both processes. Tight conservation of the HIF/prolyl hydroxylase system in Drosophila provides a new focus for understanding oxygen homeostasis in intact multicellular organisms (Lavista-Llanos, 2002).


REFERENCES

Bracken, C. P., Whitelaw, M. L. and Peet, D. J. (2003). The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell. Mol. Life Sci. 60(7): 1376-93. 12943226

Bruick, R. K. and McKnight, S. L. (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294: 1337-1340. 11598268

Bruick, R. K. (2003). Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 17(21): 2614-23. 14597660

Kaelin, W.G.Jr. (2002). How oxygen makes its presence felt. Genes Dev. 16, 1441-1445. 12080083

Lavista-Llanos, S., Centanin, L., Irisarri, M., Russo, D. M., Gleadle, J. M., Bocca, S. N., Muzzopappa, M., Ratcliffe, P. J. and Wappner, P. (2002). Control of the hypoxic response in Drosophila melanogaster by the basic helix-loop-helix PAS protein Similar. Mol. Cell. Biol. 22: 6842-6853. 12215541

Salceda, S. and Caro, J. (1997). Hypoxia-inducible factor 1alpha (HIF-

Semenza, G.L. (2001). HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107: 1-3. 11595178


date revised: 10 July 2004

Developmental Pathways conserved in Evolution

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