UNIVERSITY OF MALTA
RESEARCH SEMINARS
Abstract form
Title: The Hypoxia Inducible Factors
Presenter: Steve Bonello
Contact address: Experimentelle Kinderkardiologie, Deutsches Herzzentrum,
Lazarettstr 36, 80636 München, Deutschland
Tel: 0049 89 1218 2705
Fax:
Email: sbonello.geo@yahoo.com
Presentation date: 19th December 2005
Abstract
The hypoxia inducible factors (HIF1, HIF2 and HIF3) are a family of transcription
factors activated by low oxygen tension. They are essential for the normal
development of the circulatory system. However, HIF activation in a number of
pathological conditions is correlated with worse prognosis. The HIF proteins are
heterodimers composed of a tightly regulated alpha subunit and a constituitively
expressed beta subunit (also known as Aryl Nuclear Translocator protein, ARNT).
HIF1α and HIF2α have been well characterised and shown to be regulated mostly
at the protein level via oxygen dependent degradation under normoxia. At low
oxygen levels the alpha subunit is stabilised and forms a heterodimer with ARNT.
This is followed by DNA binding and formation of the transcription complex to bring
about the gene expression. HIF3α is the last member of this family to be discovered
and is structurally similar to HIF1α and HIF2α. Coimmunoprecipitation and
bimolecular fluorescence assay showed that HIF3α is a novel interaction partner for
both ARNT and HIF1α. Luciferase reporter gene assays showed that expression of
HIF3α results in downregulation of HIF activity. Furthermore, endothelial cells
expressing HIF3α showed decreased proliferation and reduced angiogenic activity
under stimulation. HIF3α is therefore an inhibitory component of the HIF pathway.
Interestingly, we found that non-hypoxic stimuli such as thrombin are also able to
activate HIF1α. Luciferase reporter gene assays using deletion constructs from the
HIF1α promoter revealed that an NFκB site was a major determinant for this
upregulation. Since NFκB is an inflammatory mediator whose activity is related to
oxidative stress, we investigated the link between these two transcription factors.
Our studies showed that thrombin is able to increase HIF1α levels through a redox
sensitive mechanism in which NFκB is activated and brings about expression of
HIF1α by binding to its promoter. Together these studies show novel mechanisms
by which the HIF pathway is regulated and may offer new therapeutic strategies to
modify the pathological course of a number of diseases where HIF activation is
undesirable.