Benjamin Vogel

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B1 STAT-Activation in T-cell growth transformation

Principal investigator
Armin Ensser

Mentor
Alexander Steinkasserer

PhD exam: 18.02.2013

Initial events in T-cell growth transformation by Herpesvirus saimiri (HVS)

Herpesvirus saimiri (HVS) induces T-cell lymphoma in New World primates. HVS subgroup C strains also growth transform human T-cellsin vitro The viral effector oncoproteins Tip and StpC influence cellular signalling pathways. STAT3 andspecifically STAT5 signalling pathways are activated in HVS transformed T-cell lines. The protein tyrosine kinase Lck, a key regulator of T-cell activation, binds to and phosphorylates the viral effector Tip. Two defined mutations of Tip can direct the phosphorylation and activation of either STAT3 or STAT5 by Lck.
The constitutive STAT3 activation in HVS-wild type infected T-cells is dispensable for T-cell growth transformation. In contrast, STAT5 activation is required, as mutation of the major Tip tyrosine phosphorylation site made cells dependent on exogenous interleukin-2. This growth factor requirement correlated with STAT5 phosphorylation by Lck and Tip. Thus, we assume that, for viral transformation, Tip preferentially targets STAT5.
The project will investigate how the STAT5 pathway, which is central for T-cell growth and homeostasis, is reprogrammed by the viral effector Tip. This will be addressed by studies with inhibitors, knockdown experiments and dominant-negative molecules, and by monitoring the cells deprived of the respective signalling pathway. We will further investigate whether STAT5 activation is required only in initiation or further in the maintenance of viral transformation. A murine H-2Kk MHC class I alloantigen (expressed on nucleated cells from mice of the H-2K haplotype) is expressed by recombinant Herpesvirus saimiri. This marker will be used to determine the infected T-cell subpopulations by multi-color flow cytometry and monitor the initial events that lead to T-cell transformation.

 

Publications

Mazumder, E. D., Jardin, C., Vogel, B., Heck, E., Scholz, B., Lengenfelder, D., Sticht, H. and Ensser A. (2012). A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip. PLoS One 7(4), e34306.

Alberter, B., Vogel, B., Lengenfelder, D., Full, F. and Ensser, A. (2011). Genome-wide histone acetylation profiling of Herpesvirus saimiri in human T cells upon induction with a histone deacetylase inhibitor. J Virol 85, 5456-5464.

Vogel, B., Full, F., Biesinger, B., Linden, C., Alberter, B. and Ensser, A. (2010). Episomal replication timing of γ-herpesviruses in latently infected cells. Virology 400, 207-214.

Lehner, M., Grillhoesl, C., Full, F., Vogel, B., Weller, P., Müller-Fleckenstein, I., Schmidt, M., Fleckenstein, B., Holter, W. and Ensser, A. (2009). Transformation efficiency by Herpesvirus saimiri is not a limiting factor in clonal CD8pos T cell outgrowth. Virology 388, 15-20.

 

Presentations

July 2012 4th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Latent infection and growth transformation of human natural killer cells by Herpesvirus saimiri
Talk
     
June 2012 International Symposium: Fourty Years of Virology at the University of Erlangen-Nürnberg, Erlangen, Germany
Latent infection and growth transformation of human natural killer cells by Herpesvirus saimiri
Poster
     
April 2012 Cold Spring Habor Meeting: Gene Expression and Signalling in the Immune System, Cold Spring Habor, New York, USA
Latent infection and growth transformation of human natural killer cells by Herpesvirus saimiri
Poster
     
October 2011 First International SFB 796 Conference: Mechanisms of viral host cell manipulations: from plants to humans, Bamberg, Germany
Latent infection and transformation of human lymphocytes by Herpesvirus saimiri
Poster
     
July 2011 3rd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Latent infection and transformation of human lymphocytes by Herpesvirus saimiri
Poster
     
September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Identification of target cells for HVS infection and transformation
Talk
     
February 2010 FEBS Special Meeting: Jak-Stat-Signalling: from Basics to Disease, Vienna, Austria
The role of STATs in virus induced T cell growth and differentiation
Poster
     
September 2009 First Annual Retreat, Erlangen School of Molecular Communication, Schloss Atzelsberg, Atzelsberg, Germany
Initial events in T-cell growth transformation by Herpesvirus saimiri (HSV)
Talk
     
March 2009 19th Annual meeting: Gesellschaft für Virologie, Leipzig, Germany
T cell transformation by Herpesvirus saimiri requires STAT5 pathways
Poster
     
July 2008 33rd Annual International Herpesvirus Workshop, Estoril, Portugal
Early replication timing of gammaherpesviruses
Poster
     
March 2008 18th Annual meeting: Gesellschaft für Virologie, Heidelberg, Germany
Episomal replication timing of gammaherpesviruses
Poster