المؤلفون: Nagy, Zsuzsanna S., Ross, Jeremy A., Rodriguez, Georgialina, Balint, Balint L., Szeles, Lajos, Nagy, Laszlo, Kirken, Robert A.

المصدر: PLoS ONE; Feb2013, Vol. 8 Issue 2, p1-11, 11p

مصطلحات موضوعية: GENOMES, GENE mapping, INTERLEUKIN-2, GENE targeting, LYMPHOCYTIC leukemia, CANCER cells, APOPTOSIS

مستخلص: IL-2 is the primary growth factor for promoting survival and proliferation of activated T cells that occurs following engagement of the Janus Kinase (JAK)1–3/and Signal Transducer and Activator of Transcription (STAT) 5 signaling pathway. STAT5 has two isoforms: STAT5A and STAT5B (commonly referred to as STAT5) which, in T cells, play redundant roles transcribing cell cycle and survival genes. As such, inhibition of STAT5 by a variety of mechanisms can rapidly induce apoptosis in certain lymphoid tumor cells, suggesting that it and its target genes represent therapeutic targets to control certain lymphoid diseases. To search for these molecules we aligned IL-2 regulated genes detected by Affymetrix gene expression microarrays with the STAT5 cistrome identified by chip-on-ChIP analysis in an IL-2-dependent human leukemia cell line, Kit225. Select overlapping genes were then validated using qRT²PCR medium-throughput arrays in human PHA-activated PBMCs. Of 19 putative genes, one key regulator of T cell receptor signaling, PDE4B, was identified as a novel target, which was readily up-regulated at the protein level (3 h) in IL-2 stimulated, activated human PBMCs. Surprisingly, only purified CD8+ primary T-cells expressed PDE4B, but not CD4+ cells. Moreover, PDE4B was found to be highly expressed in CD4+ lymphoid cancer cells, which suggests that it may represent a physiological role unique to the CD8+ and lymphoid cancer cells and thus might represent a target for pharmaceutical intervention for certain lymphoid diseases. [ABSTRACT FROM AUTHOR]

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المؤلفون: Nagy, Zsuzsanna S., Ross, Jeremy A., Rodriguez, Georgialina, Bader, Julia, Dimmock, Jonathan, Kirken, Robert A.

المصدر: FEBS Letters; Apr2010, Vol. 584 Issue 8, p1515-1520, 6p

مصطلحات موضوعية: MEMBRANE proteins, PROTEIN-tyrosine kinases, APOPTOSIS, ENZYME inhibitors, CANCER treatment, GENETIC regulation, INTERLEUKIN-2, PROTEIN microarrays, LYMPHOCYTIC leukemia

مستخلص: Abstract: In the current work, we report that specific inhibition of Janus tyrosine kinase (JAK3) via NC1153 induces apoptosis of certain leukemia/lymphoma cell lines. Affymetrix microarray profiling following NC1153 treatment unveiled JAK3 dependent survival modulating pathways (p53, TGF-β, TNFR and ER stress) in Kit225 cells. IL-2 responsive NC1153 target genes were regulated in human JAK3 positive, but not in JAK3 negative lymphoid tumor cells. Moreover, primary lymphoma samples revealed that a number of these genes were reciprocally regulated during disease progression and JAK3 inhibition suggesting that downstream targets of JAK3 could be exploited in the development of novel cancer treatment regimes. [Copyright &y& Elsevier]

: Copyright of FEBS Letters is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)