Hypoxia Group

Group leader

Panu Jaakkola
Senior Research Fellow
panu.jaakkola [at] btk.fi

Contact Information

Turku Centre for Biotechnology P.O. Box 123, BioCity
(Street adr. Tykistökatu 6 B) FIN-20521 Turku, Finland
+358-2-3338030 (Panu Jaakkola)
+358-2-333-8000 (Attn. Panu Jaakkola)

Description of the Project

Hypoxia is a common feature of solid tumors where it causes resistance to apoptosis and enhances 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 hydroxylated 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.

Clear cell carcinoma is a common form of kidney cancer 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 constitutively active in RCC. Due to the constant HIF-mediated signaling in RCC one of the PHDs, namely PHD3, is strongly upregulated in RCC.

We are investigating the functions of PHD3 in RCC and its role in regulating cell fate as well as cell cycle under hypoxic conditions. Moreover, we are characterizing other VHL-dependent changes in RCC formation .

Current topics:
PHD3 and p27 in hypoxic cell cycle regulation
Mechanisms by which hypoxia regulates survival decisions in cancer progression
Prolyl hydroxylases in renal cell carcinoma; links to defective VHL signaling
Global changes in protein and gene expression in RCC

Group Members

Post Doc:
Krista Rantanen (PhD)
Graduate students:
Heidi Högel, (M.Sci)
Petra Miikkulainen (M.Sci)

Pekka Heikkinen, (M.Sci)
Undergraduate student:
Olli Metsälä
Technician:
Taina Kalevo-Mattila

 

Rantanen K., Pursiheimo J., Högel H., Miikkulainen P., Sundström J. and, Jaakkola P.M. (2012). p62/SQSTM1 regulates hypoxia response by attenuating normoxic PHD3 activity through aggregate sequestration and enhanced degradation. J Cell Sci. Jan 23.

Högel H., Rantanen K., Jokilehto T., Grenman R. and, Jaakkola P.M. (2011). Prolyl hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells. PloS One 6(11):e27112

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.

Heikkinen P.T., Nummela M., Leivonen S.K., Westermarck J., Hill C.S., Kähäri V.-M., Jaakkola P.M. (2010). Hypoxia activated Smad3-specific dephosphorylation by PP2A. (2010).  J Biol.Chem.285(6):3740-9.

Jokilehto T., Högel H., Heikkinen, P., Rantanen K., Elenius, K., Sundström J., Jaakkola P.M. (2010). Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth. Exp. Cell Res.  316(7):1169-78.

Pursiheimo J., Rantanen K., Heikkinen P.T., Johansen T., Jaakkola P.M. (2009). Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene28(3):334-344.

Luukkaa M., Jokilehto T, Kronqvist P., Vahlberg, T., Grénman, R., Jaakkola P. and Minn, H. (2009). Expression of the cellular oxygen sensor PHD2 (EGLN-1) predicts radiation sensivity in squamous cell cancer of the head and neck. Int J Radiat Biol. Jul 9:1-9.

Rantanen K., Pursiheimo J., Högel H., Himanen V., Metzen E., Jaakkola P.M. (2008) Prolyl Hydroxylase 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.

Epstein, A.C.R., Gleadle, J.M., McNeill, L.A., Hewitson, K.S., O’Rourke, J., Mole, D.R., Mukherji, M., Metzen, E., Wilson, M.I., Dhanda, A., Tian, Y.-M., Masson, N., Hamilton, D.L., Jaakkola, P., Barstead, R., Hodgkin, J., Maxwell, P.H., Pugh, C.W., Schofield, C.J., Ratcliffe, P.J. (2001). C.elegans EGL-9 and mammalian homologues define a family of dioxygenases that regulate HIF through prolyl hydroxylation. Cell 107; 43-54.

Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M.I., Gielbert, J., Gaskell, S.J., Kriegsheim, Av, Hebestreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292; 468-72.

Reviews
Jaakkola P.M., Rantanen K. (2013) The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3. Biol Chem. Apr;394(4).

Jokilehto T., Jaakkola P.M. (2010) The role of HIF prolyl hydroxylases in tumor growth. J Cell Mol Med. 14(4):758-70.

Jaakkola P.M., Pursiheimo JP. (2009) p62 degradation by autophagy: Another way for cancer cells to survive under hypoxia.  Autophagy. Apr 16;5(3).

Funding

Turku University Hospital, Cancer Research Foundation of Finland, Sigrid Juselius Foundation and Finnish Cultural Foundation