Signalling Pathways
Signalling Pathways Regulated by Oncogenic Pim Kinases
Group Leader
Päivi Koskinen, PhD, Adj. Prof. in Molecular and Cell Biology
Contact information
Email: firstname.surname@btk.fi
Tel. +358-2-333 8044 (Senior Group Leader at CBT)
Tel. +358-2-333 5936 (Senior Assistant at Dept. of Biology)
Tel. +358-2-333 8045 (Laboratory at CBT)
Fax: +358-2-333 8000
Mailing address: Turku Centre for Biotechnology, BioCity Turku, 5th floor, Tykistökatu 6B, 20520 Turku, FINLAND
Personnel
- Eeva Rainio, PhD, postdoctoral fellow
- Jouko Sandholm, MSc, graduate student
- Riitta Vahakoski, MSc, graduate student
- Niina Tiensuu, MSc, graduate student
- Juho Virtanen, BSc, undergraduate student
- Sini Eerola, BSc, undergraduate student
- Heidi Ekman, BSc, undergraduate student
Project description
One of the strongest pieces of evidence for oncogene cooperation has been obtained from transgenic mice overexpressing the c-myc and pim-1 oncogenes. These mice produce lymphomas at a very early stage and often die already in utero. The major aim of our studies is to establish a mechanistic model for the cooperation between the c-myc-encoded transcription factor and the pim-1-encoded serine/threonine-specific protein kinase. For this purpose, we have used the yeast two-hybrid system as well as phosphoproteomics to identify proteins that can physically interact with Pim-1 and which may thereby either regulate or mediate its functions. By this approach, we hope to be able to reaveal whether Pim-1 is involved in any known signal transduction pathway or in a novel pathway that can more specifically complement c-myc overexpression to induce lymphoid malignancies. We also wish to determine whether Pim kinases can protect not only hematopoietic, but also neuronal cells from apoptotic death.
Sequencing of the Pim-1-interacting clones has revealed several interesting proteins involved in signaling within the immune system or the central nervous system. Moreover, many of these proteins appear to be good in vitro substrates for Pim-1. Several functional assays are under way to investigate the physiological relevance of the observed protein-protein interactions between Pim-1 and its putative substrates. Overall, our studies are expected to increase general understanding about signalling mechanisms controlling cell growth, differentiation as well as death both in normal and in transformed hematopoietic or neuronal cells.
Selected publications
- Peltola KJ, Hollmén M, Maula SM, Rainio EM, Ristamäki R, Luukkaa M, Sandholm J, Sundvall M, Elenius K, Koskinen PJ, Grenman R & Jalkanen S. Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor. Neoplasia 11, 629-636, 2009.
- Cheng F, Weidner-Glunde M, Varjosalo M, Rainio EM, Lehtonen A, Schulz TF, Koskinen PJ, Taipale J & Ojala PM. KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA. PLoS Pathogens, 5, e1000324, 2009.
- Aho TLT, Sandholm J, Peltola KJ, Ito Y & Koskinen PJ. Pim-1 kinase phosphorylates RUNX family transcription factors and enhances their activity. BMC Cell Biol. 7, 1-9, 2006.
- Aho TLT, Ylikoski E, Lund R, Matikainen S, Lahesmaa R & Koskinen PJ. Expression of human pim family genes is selectively upregulated by cytokines promoting Th1, but not Th2 cell differentiation. Immunol. 116, 82-88, 2005.
- Glazova M, Aho TLT, Palmetshofer A, Murashov A, Scheinin M & Koskinen PJ. Pim-1 kinase enhances NFATc activity and neuroendocrine functions in PC12 cells. Mol. Brain Res. 138, 116-123, 2005.
- Rainio EM, Ahlfors H, Carter K, Ruuska M, Matikainen S, Kieff E & Koskinen PJ. Pim kinases are upregulated by Epstein-Barr virus infection and enhance EBNA2 activity. Virol. 333, 201-206, 2005.
- Peltola KJ, Paukku K, Aho TLT, Ruuska M, Silvennoinen O & Koskinen PJ. Pim-1 kinase inhibits Stat5-dependent transcription via its interactions with SOCS1 and SOCS3. Blood 103, 3744-3750, 2004.
- Aho TLT, Sandholm J, Peltola KJ, Mankonen H, Lilly M & Koskinen PJ. Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett. 571, 43-49, 2004.
- Yan B, Zemskova M, Kraft A, Koskinen PJ & Lilly M. The Pim-2 kinase phosphorylates Bad on serine-112 and reverses Bad-induced cell death. J. Biol. Chem. 278, 45358-45367, 2003.
- Thompson J, Peltola KJ, Koskinen PJ, Jänne OA & Palvimo JJ. Attenuation of androgen receptor-dependent transcription by the serine/threonine kinase Pim-1. Lab. Invest. 83, 1301-1309, 2003.
- Rainio EM, Sandholm J & Koskinen PJ. Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase. J. Immunol. 168, 1524-1527, 2002.
- Eichmann A, Yuan L, Bréant C, Alitalo K & Koskinen PJ. Developmental expression of Pim kinases suggests functions also outside of the hematopoietic system. Oncogene 18, 4022-4031, 1999.
- Lilly M, Sandholm J, Cooper JJ, Koskinen PJ & Kraft A. The Pim-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway. Oncogene 18, 4022-4031,1999.
- Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, Eisenman RN & Ness SA. Pim-1 kinase and p100 cooperate to enhance Myb activity. Mol. Cell 2, 417-425, 1998.