Oxygen sensing molecules in kidney cancer

​Description of Research

Hypoxia is a common feature of solid tumors where it causes resistance to apoptosis and en-hances tumor growth and metastasis. On cellular level the main component regulating responses to hypoxia is a transcription factor termed hypoxia-inducible factor (HIF). HIF in turn is hy-droxylated by prolyl hydroxylase enzymes (PHD) 1-3 leading to targeting of HIF for proteasomal degradation by von Hippel-Lindau tumor suppressor protein (pVHL). PHDs may control cancer growth by targeting other molecular targets besides HIF.

Renal clear cell carcinoma (ccRCC). is a common form of kidney cancer and has a poor prognosis at advanced stage characterized by loss of function of pVHL. Defective function of pVHL leads to ablation of the proteolytic regulation of HIF thus making hypoxia signaling pathways constitu-tively active in RCC. Due to the constant HIF-mediated signaling in RCC one of the PHDs, namely PHD3, is strongly upregulated in RCC.

The group investigating the functions of PHDs in ccRCC and their role in regulating cell fate as well as cell cycle under hypoxic conditions having a focus on PHD3 isoform. The group has re-vealed a critical role for PHD3 in ccRCC development e.g. in cell cycle progression and autophagy. Besides PHDs, the group studies other VHL-dependent molecular changes in RCC formation.

Members of the reserach group

Krista Rantanen, PhD
Heidi Högel, Msci
Petra Miikkulainen, Msci
Olli Metsälä, Msci
Taina Kalevo-Mattila, technician

Selected Publications

Högel H., Miikkulainen P., Bino L. and Jaakkola P.M. (2015). Hypoxia inducible prolyl hydrox-ylase PHD3 maintains carcinoma cell growth by decreasing the stability of p27.. Mol Cancer. 2015 Jul 30;14(1):143

Rantanen K., Pursiheimo J., Högel H., Miikkulainen P., Sundström J. and, Jaakkola P.M. (2013). p62/SQSTM1 regulates cellular oxygen sensing by attenuating normoxic PHD3 activity through aggregate sequestration and enhanced degradation. J Cell Sci Mar 1;126(Pt 5):1144-54.

Heikkinen P., Nummela M., Kähäri V.M. and Jaakkola  P.M. (2010). Hypoxia converts Smad7 from tumor suppressor into tumor promoter. Cancer Res., 70(14):5984-93

Rantanen K., Pursiheimo J., Högel H., Himanen V., Metzen E., Jaakkola P.M. (2008) Prolyl Hy-droxylase PHD3 Activates Oxygen-dependent Protein Aggregation. Mol Biol Cell 19(5):2231-40.

Jokilehto, T., Rantanen, K., Luukkaa, M., Heikkinen, P., Grenman, R., Minn, H., Kronqvist, P., Jaakkola P.M. (2006). Overexpression and nuclear translocation of HIF prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma associates with tumor aggressiveness. Clin Cancer Res 12(4):1080-1087


 Docent Panu Jaakkola