Browsing by Author "Pinkert, D."

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    STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis
    (Nature Publishing Group, 2005)
    Holtick, U.
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    Vockerodt, Martina
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    Pinkert, D.
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    Schoof, Nils
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    Sturzenhofecker, B.
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    Kussebi, N.
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    Lauber, Kirsten
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    Wesselborg, S.
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    Loffler, D.
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    Horn, F.
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    Truemper, Lorenz H.  
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    Kube, Dieter
    Classical Hodgkin lymphoma ( cHL) is a distinct malignancy of the immune system. Despite the progress made in the understanding of the biology of cHL, the transforming events remain to be elucidated. Recently, we demonstrated that the Janus kinase inhibitor AG490 blocked cellular proliferation and STAT3 phosphorylation in cHL. To explore the potential of constitutively activated STAT3 as a drug target and its role in cHL pathogenesis, different cHL cell lines were analyzed. Treatment of cHL cells by the protein tyrosine kinase inhibitor AG17 was associated with inhibition of cellular proliferation and cell cycle arrest. AG17 treatment was accompanied by decreased levels of STAT3 phosphorylation, whereas NF- kappa B and p38/ SAPK2 signaling were not inhibited. Incubation with AG17 or AG490 sensitized cHL cells to CD95/ Fas/ Apo- 1 or staurosporine-mediated apoptosis. Coincubation of tyrphostins with staurosporine was accompanied by rapid complete inhibition of STAT3 phosphorylation. RNA interference directed against STAT3 in L428 and L1236 cHL cells demonstrated that STAT3 is essential for cell proliferation of these cHL cells. In conclusion, these findings support the concept that STAT3 signaling is important in the pathogenesis of cHL and tyrphostins are agents for developing new therapeutic strategies.
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    The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: Importance of mRNA half-life regulation
    (Wiley-liss, 2005)
    Vockerodt, Martina
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    Pinkert, D.
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    Smola-Hess, S.
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    Michels, A.
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    Ransohoff, Richard M.
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    Tesch, H.
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    Kube, Dieter
    The latent membrane protein 1 (LMP1) of Epstein-Barr Virus (EBV) is the main inducer of immuno-modulatory molecules affecting growth and survival of EBV-infected cells. However, the network of signalling pathways involved remains to be elucidated. Here we show that LMP1 may regulate cellular genes like IFN-gamma-inducible protein-10 kDa (IP-10) not only through transcriptional but also post-transcriptional mechanisms. LMP1-mediated IP-10 expression is independent from IFN-gamma, TNF-alpha or IL-18. Transcriptional activation of IP-10 by LMP1 or CD40 stimulation depends on an NF-KB motif within the proximal 435 bp fragment. Carboxy-terminal activating regions 1 or 2 of LMP1 are sufficient to direct IP-10 promoter activation. IP-10 induction is inhibited by blockade of p38/SAPK2 with SB 202190, which results in decreased IP-10 mRNA half-life without affecting IP-10 promoter activity. Thus, LMP1-mediated p38/SAPK2 activation regulates transcript stability. This new mechanism of gene regulation demonstrates the potential of the oncoprotein LMP1 to orchestrate a network of signalling pathways at different regulatory levels including mRNA stability. (C) 2004 Wiley-Liss, Inc.