Regulation of TGF-β signaling by Xrel3, a member of the Rel/NF-κB family in human cervical cancer cells

Green, Adam Geoffrey (2003) Regulation of TGF-β signaling by Xrel3, a member of the Rel/NF-κB family in human cervical cancer cells. Masters thesis, Memorial University of Newfoundland.

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    Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
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Abstract

The Rel/NF-κB and TGF-βSMAD signal transduction pathways are essential for maintaining homeostasis, controlling cell proliferation and survival in every species studied and in many different cell and tissue types. Both pathways are implicated in numerous cancers resulting from their abnormal regulation. For instance, constitutive Rel/NF-κB activity leads to continous pro-survival stimulation allowing cancer cells the opportunity to continue growing in otherwise detrimental conditions. Also, due to its role in growth suppression, TGF-β-insensitivity has been reported in a majority of tumor types. Until recently, however, very few studies have attempted to determine whether there are interactions between the signaling members of each of these pathways. Therefore, this study was designed for this purpose. -- The tetracycline-inducible system (Tet-On) was chosen to control the expression of a constitutively active Rel/NF-κB member, Xrel3, in CaSki human cervical carcinoma cell lines. The responses to TGF-β stimulation were measured in Xrel3-expressing and non- expressing CaSki cells to investigate whether the presence of Xrel3 affects TGF-β signaling. This thesis provides evidence that Xrel3 is able to block the TGF-β-induced growth inhibition, and PAI-1 and p21 induction, but not SMAD2 phosphorylation or p15 induction in CaSki cervical cancer cells. A mutated form of Xrel3, mutNLS, was not able to affect TGF-β responses of growth inhibition or marker induction. These results suggest that constitutive Rel/NF-κB activity may be responsible for the loss of sensitivity to TGF-β and may provide insight for therapeutic strategies for treating tumors which display this activity.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/6978
Item ID: 6978
Additional Information: Bibliography: leaves 103-126.
Department(s): Medicine, Faculty of
Date: May 2003
Date Type: Submission
Library of Congress Subject Heading: Cervix uteri--Cancer; Cellular signal transduction
Medical Subject Heading: Cervix Neoplasms; Signal Transduction

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