MgcRacGAP interacts with HIF-1alpha and regulates its transcriptional activity.
HIF-1alpha is the inducible subunit of the dimeric transcription factor HIF-1 (Hypoxia Inducible Factor 1). It is induced by hypoxia and hypoxia-mimetics in most cell types, as well as non-hypoxic signals such as growth factors, cytokines and oncogenes, often in a cell specific manner. HIF-1 is present in virtually all cells of higher eukaryotes and its function is of great biomedical relevance since it is highly involved in development, tumor progression and tissue ischemia. Intracellular signaling to HIF-1alpha, as well as its further action, involves its participation in numerous protein complexes. Using the yeast two-hybrid system we have identified MgcRacGAP (male germ cell Rac GTPase Activating Protein) as a HIF-1alpha interacting protein. The MgcRacGAP protein is a regulator of Rho proteins, which are principally involved in cytoskeletal organization. We have verified specific binding of HIF-1alpha and MgcRacGAP in vitro and in vivo in mammalian cells. We have additionally shown that MgcRacGAP overexpression inhibits HIF-1alpha transcriptional activity, without lowering HIF-1alpha protein levels, or altering its subcellular localization. Moreover, this inhibition is dependent on the MgcRacGAP domain that interacts with HIF-1alpha. In conclusion, our findings demonstrate that HIF-1alpha function is negatively affected by its interaction with MgcRacGAP.
Lyberopoulou
Aggeliki
A
Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Venieris
Emmanouil
E
Mylonis
Ilias
I
Chachami
Georgia
G
Pappas
Ioannis
I
Simos
George
G
Bonanou
Sofia
S
Georgatsou
Eleni
E
D000818:Animals; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000166:cytology; D013347:Subcellular Fractions; D013816:Thermodynamics; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020690:GTPase-Activating Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C115995:mgcRacGAP; D008156:Luciferases