Members of the group

• Elitsa Dimova, PhD
• Daniela Flügel, PhD
• Anatoly Samoylenko, PhD (Sigrid Juselius Foundation)
• Anna-Kaisa Lappi, PhD
• Tina Horbach, Dipl. Chem.
• Teija Paakkola, M.Sc.

Research projects

Background
Adaptation to changes in the ambient O2 tension is essentially required for the adaequate energy supply of humans and all other aerobic living organisms. Disturbances in the O2- and nutrient supply will have profound effects on not only cellular but also whole body function and may contribute to the development of various diseases like cancer, liver fibrosis, diabetes mellitus, the metabolic syndrome, artherosclerosis and thrombosis as well as pulmonary hypertension. These pathologies are also associated with high expression levels of plasminogen activator inhibitor-1 (PAI-1) indicating a bad prognosis.
We have shown that oxygen gradients, e.g. the periportal to perivenous drop of oxygen within the liver acinus, modulate the transcription of key regulatory genes. Thereby, we have demonstrated that hypoxia and insulin activate PAI-1 transcription maximally via a transcriptional complex consisting of hypoxia-inducible factor-1 (HIF-1). In addition, this factor together with hepatocyte nuclear factor 4 (HNF-4) and the coactivator p300, was also involved in the transcriptional activation of the glucokinase (GK) gene; which could be downregulated by FoxO. Within this scenario it appeared that especially stabilization of HIF-1a by insulin occurred via the PKB/GSK-3 pathway where we found that GSK-3 can directly phosphorylate HIF-1a. These factors displayed an association with different cellular compartments like the endoplasmic reticulum, the Golgi complex or the mitochondria indicating a role of these compartments in redox signalling.
We also could show that induction of PAI-1 by HIF-1 was competed by another transcription factor, namely upstream stimulatory factor-2 (USF-2). Since enhanced PAI-1 and HIF-1 levels are not only associated with the metabolic syndrome but also associated with tumor progression these data implicated a role for USF as tumor suppressor.

Aims
Our further investigations are aiming to investigate the role of oxygen (i) on the hemostasis-, diabetes- and tumor-associated gene expression with special emphasis to plasminogen activator inhibitor-1 (PAI-1) expression, (ii) on nutrient, hormone and oxidative stress regulated transcription factors (e.g. FoxOs, NFkB) and signaling pathways as well as their possible cross-talk with hypoxia-inducible factors (HIFs), (iii) on the signaling between different cellular compartments and (iv) the detailed molecular mechanisms involved in USF-dependent tumor inhibition.
To achieve these aims, we use multi- and interdisciplinary research efforts using the latest techniques of life science research, including biochemical, immunological, molecular and cell biological techniques as well as genetically modified cells and animals. Together, these experiments may help to better understand the regulatory phenomena of hypoxia and to develop new therapeutic and preventive approaches for those associated diseases.

Publications

To access an actual publication list please follow this link through Pubmed.