NFATc1/A: ein außergewöhnliches NFAT-Protein mit anti-apoptotischen Eigenschaften und onkogenem Potential

• Applicant: Dr. Sergei Chuvpilo
• Subject Area: Pathology
• Term: from 2004 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5434543

• Final Report Year: 2008

Final Report Abstract

Unsere experimentellen Arbeiten zur Synthese und Funktion von NFATc1/alphaA haben interessante Einblicke in die Autoregulation der NFATc1/alphaA-Synthese und erste Daten zu den molekuklaren Mechanismen der anti-apoptotischen Wirkung dieses NFATcl-Protein geliefert. Negative Befunde über die cancerogene Wirkung von NFATc1/alphaA in somalischen Zellen (unpubl. Befunde) haben uns davon abgehalten, transgene Mäuse zur Uberexpression von NFATc1/Alpha zu etablieren, sondern uns auf die konditionelle Inaktivierung der NFATc1-Expression zu konzentrieren. Während Mäuse zur generellen Inaktivierung der NFATc1-Expression vorliegen, haben wir ES-Zell-Linien etabliert, die die individuelle Inaktivierung entweder des P2 oder P1 Promotors erlauben. In Zusammenarbeit mit der Zentralen Tierversuchseinrichtung der Universität Mainz werden diese z.Z. in Blastocysten injiziert und wir hoffen, damit Keimbahn-Transmissionen zu erhalten. Solche Tiere sollten die besten "Tools" darstellen, die Funktion der NFATc1/alphaA weiter zu untersuchen.

Publications

• Akimzhanov.A., Krenacs, L, Schlegel,T.,Klein-Hessling,S., Bagdi.E., Stelkovics.E., Kondo.E., Chuvpilo.S., Wilke, P., Avots, A., Gattenlöhner, S., Müller-Hermelink,H.-K., Palmetshofer.A. and Serfling, E., Epigenetic changes and suppression of the NFATC1 promoter in human lymphomas with defects in immunoreceptor signalling. American J. Pathol.172, 216-225 (2008).
  
  
• Asagiri.M., Sato.K., UsamiJ., Ochi.S., Nishina.H., Yoshida.H., Morita,!., Wagner.E.F., Mak.T.W., Serfling,E., and Takayanagi, H., Autoamplification of NFATd determines its essential role in bone homeostasis. J. Exp. Med. 202,1261-1269 (2005).
  
  
• Berberich-Siebelt.F., Berberich,!., Santner-Nanan, B., Jha, M.K., Andrulis.M., Klein- Hessling.S., Schimpl, A.and Serfling.E., SUMOylation interferes with CCAAT/Enhancer-bindingt protein ß-mediated c-myc repression, but not IL-4 activation in T cells. J. Immunol. 176,4843-4851 (2006).
  
  
• Bopp.T., Becker.C., Klein.M., Klein-Heßling.S., Pa!metshofer,A., Serfling, E., Heib, V., Becker.M., Kubach, J., Schmrtt, S., Stoll.S., Schild.H., Staege,M., Stassen,MM Jonulert.H., and Schmitt, E., Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204:1303-1310 (2007).
  
  
• BoppJ., PalmetshoferA, Serfling.E., Heib,V., Schmitt, S., Richter, C., Klein, M., Schild, H., Schmitt, E. and Stassen.M., NFATc2 und c3 transcription factors play a crucial role in suppression of CD4* T lymphocytes by CD4*CD25* regulatory T cells. J. Exp. Med. 201, 181-187(2005).
  
  
• Buttmann,M., Berberich-Siebelt.F., Serfling.E., and Rieckmann,P., Interferon-ß is a potent inducer of interferon regulatory faclor-1/2-dependent IP-10/CXCL10 expression in primary human endothelial cells. J. of Vascul. Res. 44, 51-60 (2007).
  
  
• Floess.S., Freyer.J., Siewert,C. Baron.U., Olek.S., Polansky.J., Schlawe.K., Chang,H.-D., Bopp.T., Schmitt,E., Klein-Hessling, S., Serfling.E., Hamann.A, and Huehn.J., Epigenetic Control of the foxp3 locus in regulatory T cells. PLoS Biology, 5 (2), e38 (2007).
  
  
• Klein.M., Klein-Hessling.S., Palmetshofer,A, Serfling, E., Bopp.T., Heib.V., Becker, M., Taube, C., Schild,H., Schmitt.E., and Stassen.M., Specific and redundant role for NFAT transcription factors in the expression of mast cell-derived cytokines. J. Immunol. 177, 6667-6674 (2006).
  
  
• Nurieva, R.I., Chuvpilo, S., Wieder, E.D., Elkon, K. B, Locksfey, R., Serfling, E., and Dong, C., A costimulation-inititated signaling pathway regulates NFATcl transcripition in T lymphocytes. J. lmmunol.179,1096-1103(2007).
  
  
• Patra, A.K., Drewes, T., Engelmann, S., Chuvpilo, S., Kishi, H., Hünig, T., Serfling.E., and Bommhardt, U., PKB rescues calcineurin/NFAT induced arrest of rag expression and pre-T cell differentiation. J. Immunol. 177,4567-4576 (2006).
  
  
• Samanta, D.N., Palmetshofer, A., Marinkovic, D., Wirth, T., *Serfling,E. and *Nitschke, L, B cell hyperresponsiveness and expansion of follicular B cells, but not of marginal zone B cells in NFATc2/c3-double deficient mice. J. Immunology 174,4797-4802 (2005).
  
  
• Serfling, E., Berberich-Siebelt, F., and Avots, A., NFAT in Lymphocytes - a Factor for all Events? Science STKE 2007, pe42.
  
  
• Serfling, E., Klein-Hessling.S., Palmetshofer, A., Bopp, T, Stassen.M. and Schmitt.E., NFAT Transcription Factors in Control of Peripheral T Cell Tolerance. Eur. J. Immunol. 36, 2837-2843 (2006).
  
  
• Serfling.E., Chuvpilo.S., Liu.J., Höfer, T. and Palmetshofer, A. NFATc! autoregulation: A critical step for T cell fate determination. Trends in Immunol. 10,461-469 (2006).
  
  
• Sieber, M., Karanik, M., Brandt,C., Blex.C., Podtschaske, M., Erdmann.F., Rost.R., Serfling.E., Liebscher.J., Patzel.M., Radbruch.A., Fischer.G., and Baumgrass, R., Inhiition of calcieneurin-NFAT signaling by the pyrazolopyrimidine compound NCI3. Eur. J. Immunol. 37: 2617-2626 (2007).
  
  
• Stassen, M., Klein, M., Bopp, T., Neudörfl, C., Richter, C., Heib, V., Klein-Hessling, S., Serfling,E., Schild.H., and Schmitt, E., p38 MAP kinase drives the expression of mast cell-derived IL-9 via activation of the transcription factor GATA-1. Mol. Immunonology, 44: 926-933 (2007).
  
  
• Zoffmann.S., Sorensen,A.B., Andrulis.M., Wang.B., Kondo.E., Krenacs.L, Stelkovics.E., Wabl.M., Serfling, E., PalmetshoferA, and Pedersen.F.S., A tumor suppressor function for NFATcS in T cell lymphomagenesis by murine leukemia virus. Blood 106, 3546-3552 (2005).