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Titel: Microarray analysis of differentially regulated genes in human leukemia cells after expression of the inositol 5-phosphatase SHIP
Sprache: Englisch
Autor*in: García Palma, Lizet Elena
Erscheinungsdatum: 2006
Tag der mündlichen Prüfung: 2006-05-19
Zusammenfassung: 
The SH2-containing inositol 5-phosphatase SHIP-1 (SHIP) is a negative regulator of signal transduction in hematopoietic cells. It has been shown that the human T cell leukemia cell line Jurkat does not express SHIP. Restoration of SHIP expression leads to the inactivation of the PI3K/Akt signal transduction pathway and the prolongation of the G1 phase of the cell cycle. The first aim of this study was to investigate the differential expression of genes after restoration of SHIP expression in Jurkat cells. Microarray analysis revealed that restoration of SHIP expression resulted in statistically significant changes (2.0-fold cut off) in the expression levels of 37 unique mRNAs. The second aim was the validation of the differentially expressed transcripts by quantitative real-time RT-PCR. Eleven of the genes showed statistically significant transcriptional regulation (2-fold cut off) by SHIP. The third aim was to study the biological effect of the identified SHIP-regulated genes. Because the Krüppel-like transcription factor 2 (KLF2) is involved in quiescence in naïve T-cells and in regulation of Jurkat T leukemia cell growth, and SHIP leads to an inhibition of proliferation in these cells, the SHIP-mediated regulation of KLF2 in Jurkat T cells was of particular interest. KLF2 was up-regulated two to threefold at the RNA and protein level after the induced expression of SHIP. KLF2 or SHIP expression in Jurkat cells caused 45% or 60% reduction of proliferation, respectively. SHIP induction up-regulates KLF2 expression, implicating KLF2 in the SHIP-mediated reduction of proliferation in Jurkat cells. A fourth aim of this study was to determine if the regulation of KLF2 is directly regulated by the PI3K/Akt pathway. Inhibition of PI3-kinase with wortmannin in Jurkat T-cells and silencing of Akt1 expression by RNAi led to an increase in the expression of KLF2 protein levels, respectively. The data confirmed the role of the PI3K/Akt signaling pathway in the up-regulation of KLF2 in Jurkat T cells. This study contributes to the elucidation of novel factors and associations with the PI3K/Akt signaling pathway involved in the SHIP-mediated regulation of proliferation in Jurkat T cells.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/1387
URN: urn:nbn:de:gbv:18-29474
Dokumenttyp: Dissertation
Betreuer*in: Mayr, Georg W. (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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