The role of parallel signaling pathways in maintaining lymphoid cell survival

A tétel rövid nézete
dc.contributor.advisorAradi, János
dc.contributor.authorNagy, Zsuzsanna
dc.contributor.authorKirken, Robert A
dc.contributor.departmentDE -- Orvos- és Egészségtudományi Centrum -- Általános Orvostudományi Kar -- Biokémiai és Molekuláris Biológiai Intézethu
dc.contributor.departmentUniversity of Texas -- Houston Medical School -- Department of Integrative Biology and Pharmacologyhu
dc.contributor.departmentElméleti orvostudományok doktori iskolahu
dc.date.accessioned2007-06-13T15:53:43Z
dc.date.available2007-06-13T15:53:43Z
dc.date.created2002
dc.description.abstractT lymphocytes are critical for a functional immune system. However, their uncontrolled activation and growth can be manifested as a number of lymphoid derived diseases such as autoimmunity, allograft rejection, and lymphoma. Therefore, understanding the role of key signaling molecules and the ability to modify their activity in mature cells may provide new therapeutic strategies to treat T cell mediated disorders. The purpose of this study was to dissect the role of key signaling pathways activated by interleukin-2 (IL2) and other T cell growth factors that share the IL2 receptor gamma chain (γc) (IL2, 4, 7, 9, 13, 15, 21) in mediating T cell growth and survival. To accomplish this objective, antisense oligonucleotides targeted against signaling molecules including γc, Raf isoforms, Stat3, traditional pharmaceuticals to disrupt Janus tyrosine kinase 3, PI3K (wortmannin), mTor (rapamycin) and MEK kinase (PD98059) activity were utilized and their effects characterized in lymphoid cells. Antisense oligonucleotide targeted against γc inhibited protein expression (40%) in a lymphoid tumor cell line inducing apoptotic death and cell cycle arrest in G2-M phase, as measured by FACS analysis of Annexin V and Propidium Iodide stained cells. Inhibition of Jak3 (PNU156804) showed similar effects and disrupted Stat5 and MAPK activation. Novel evidence is shown here that IL2 can activate multiple isoforms of Raf, and inhibition of these isoforms by antisense oligonucleotides failed to affect cell survival or Stat5 activation. Similar results were found for inhibition of PI3K, mTor and MEK kinases. Lastly, we show that Stat3 antisense oligonucleotide treatment of a human tumor cell line bearing constitutively activated Stat3 induces cell death (40%, measured with TUNEL assay) but that IL2 can rescue these cells possibly mediated via Stat5 that becomes hyperactivated in Stat3 deleted cells. Evidence is provided that suggests Bcl2 plays key role in this cell survival process. We conclude from our findings that the Mapk, Stat and PI3K pathways likely function as separate entities in lymphoid cells, suggesting that evolutionarily these pathways might have evolved to perform specialized cell functions that may be redundant for other T cell activities. Moreover, our results suggest that Stat molecules are critical to the survival and growth of T cells and represent a therapeutically relevant target to combat T cell derived disorders.en
dc.description.bibliographyEgyetemi doktori (Ph.D.) értekezés ; University of Debrecen, Medical and Health Science Center, Faculty of Medicine, Department of Biochemistry and Molecular Biology and University of Texas at Houston Medical School, Department of Integrative Biology and Pharmacology, 2002hu
dc.description.degreePhDhu_HU
dc.format.extent88 pen
dc.format.extent255288 bytes
dc.format.extent128602 bytes
dc.format.extent2159584 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/2437/2397
dc.languageenghu
dc.language.isohuen
dc.language.isoenen
dc.rightsA kéziratos PhD munkák csak a szerzői jogok maradéktalan tiszteletben tartásával használhatókhu
dc.titleThe role of parallel signaling pathways in maintaining lymphoid cell survivalen
dc.title.subtitlethesis for the degree of Doctor of Philosophyen
dc.title.translatedPárhuzamos jelátviteli útvonalak szerepe limfoid sejtek túlélésébenen
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