The role of oxygen sensors during physiological and pathological processes in mice
Previous and Current Research
All organs in our body depend on the appropriate amount of oxygen to function. That’s why the maintenance of oxygen homeostasis at the cellular level is very important and has been the topic of many different studies. Moreover, an inadequate oxygen supply, also called hypoxia, is a prominent feature in various inflamed and/or diseased tissues, including rapidly growing tumors, healing wounds and arthritic joints. The central mediator during hypoxia is HIF (hypoxia inducible factor); a transcription factor that directly regulates genes necessary to overcome and/or resolve the negative effects of insufficient oxygen concentrations. The activity of HIF is therefore strictly regulated by a set of oxygen sensors known as the HIF-prolyl hydroxylases (PHDs). Our research group has been investigating the role of these HIF-pathway proteins during different processes in vivo.
Recently, we described for the first time that conditional loss of the most important oxygen sensor in mice, PHD2, leads to an extreme overproduction of red blood cells (polycythemia). Using different genetic approaches we found that this phenotype was exclusively dependent on the activity of the HIF2α-subunit whereas survival of these polycythemic mice was driven by HIF1α (Franke et al., Blood, 2013). Furthermore, we also revealed that PHD2 is a central mediator in the hematopoietic stem cell (HSC) compartment. Loss of this factor in these stem cells induced self-renewal in a HIF1α-dependent manner under steady-state as well as severe stress conditions (Singh et al., Blood, 2013). We also unraveled the role of PHD2 in different cancer cells during tumor development in mice. Silencing of the enzyme stimulated vessel formation, but paradoxically resulted in a profound reduction of tumor growth; an effect that relies on the anti-proliferative nature of the TGFβ signaling pathway, in a largely HIF1α-independent manner (Klotzsche-von Ameln et al., Cancer Res., 2011 and Cancer Biol Ther., 2012). In a mouse model of skin wound healing (regeneration), we demonstrated the unique expression of β3-integrin in PHD2-deficient keratinocytes, which improved healing through the enhanced migration of the epithelial layers (Kalucka et al., Mol. Cell. Biol., 2013).
Future Projects and Goals
Based on our unique collection of genetically modified mouse strains and the different in vivo models we established in the lab, we want to gain a better understanding of the interplay between the different cell types and their relation to oxygen homeostasis under physiological as well as pathological conditions. In more detail, we will study the function of the central HIF-pathway proteins during regeneration, cancer, local inflammatory disorders and hematopoiesis in mice.
Methodological and Technical Expertise
- Mouse genetics
- Tumor biology
- Inflammatory models
Mamlouk, S., J. Kalucka, R. P. Singh, K. Franke, A. Muschter, A. Langer, C. Jacob, M. Gassmann, G. B. Baretton and Wielockx, B.
Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development.
Int. J. Cancer, 15;134(4):849–58 (2014)
Kalucka, K., Ettinger, A. Franke, K., Mamlouk, S., Singh, R.P., Muschter, A., Breier, G., Katschinski, D.M., Huttner, W., Weidemann, A. and Wielockx, B.
Epithelial HIF Prolyl Hydroxylase-2 (PHD2) negatively regulates skin wound healing in mice.
Mol. Cell. Biol., 33(17): 3426–3438 (2013)
Singh, R. P., Franke K., Kalucka J., Mamlouk S., Muschter A., Gembarska A., Grinenko T., Willam C., Naumann R., Anastassiadis K., Stewart A. F., Bornstein S., Chavakis T., Breier G., Waskow C., and Wielockx B.
HIF-prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress.
Blood. 121(26):5158–5166 (2013)
Franke, K., Kalucka, J., Soulafa Mamlouk, S., Singh, R.P., Muschter, A., Weidemann, A., Iyengar, V., Jahn, S., Wieczorek, K., Geiger, K., Muders, M., Sykes, A.M., Poitz, D., Ripich, T., Otto, T., Bergmann, S., Breier, G., Baretton, G., Fong, G., Greaves, D.R., Bornstein, S., Chavakis, T., Fandrey, J., Gassmann, M., and Wielockx, B.
HIF-1α is a Protective Factor in Conditional PHD2 Deficient Mice Suffering from Severe HIF-2α-Induced Excessive Erythropoiesis.
Blood, 121(8):1436–1445 (2013)
Klotzsche-von Ameln, A., Muschter, A., Mamlouk, S., Kalucka, J., Prade, I., Franke, K., Rezaei, M., Poitz, D.M., Breier, G., and Wielockx, B.
Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Anti-Proliferative Activity of TGFβ.
Cancer Res., 1;71(9):3306–16 (2011)