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Nuclear factor {kappa}B-dependent gene expression profiling of Hodgkins disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity

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Official URL:https://doi.org/10.1084/jem.20020062
PubMed:View item in PubMed
Creators Name:Hinz, M. and Lemke, P. and Anagnostopoulos, I. and Hacker, C. and Krappmann, D. and Mathas, S. and Doerken, B. and Zenke, M. and Stein, H. and Scheidereit, C.
Journal Title:Journal of Experimental Medicine
Journal Abbreviation:J Exp Med
Page Range:605-617
Date:2 September 2002
Keywords:Oncogene, Tumor Suppressor, Survival, Chromatin, Microarray
Abstract:Constitutive nuclear nuclear factor (NF)-{kappa}B activity is observed in a variety of hematopoietic and solid tumors. Given the distinctive role of constitutive NF-{kappa}B for Hodgkin and Reed-Sternberg (HRS) cell viability, we performed molecular profiling in two Hodgkin's disease (HD) cell lines to identify NF-{kappa}B target genes. We recognized 45 genes whose expression in both cell lines was regulated by NF-{kappa}B. The NF-{kappa}B-dependent gene profile comprises chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors, the majority of which maintain a marker-like expression in HRS cells. Remarkably, we found 17 novel NF-{kappa}B target genes. Using chromatin immunoprecipitation we demonstrate that NF-{kappa}B is recruited directly to the promoters of several target genes, including signal transducer and activator of transcription (STAT)5a, interleukin-13, and CC chemokine receptor 7. Intriguingly, NF-{kappa}B positively regulates STAT5a expression and signaling pathways in HRS cells, and promotes its persistent activation. In fact, STAT5a overexpression was found in most tumor cells of tested patients with classical HD, indicating a critical role for HD. The gene profile underscores a central role of NF-{kappa}B in the pathogenesis of HD and potentially of other tumors with constitutive NF-{kappa}B activation.
Publisher:Rockefeller University Press (U.S.A.)
Item Type:Article

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