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1. Pawar, Pritish Subhash. Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma.

Degree: PhD, 2008, University of Alabama – Birmingham

Cholangiocarcinoma, a fatal tumor arising from biliary epithelium, has very poor 5-year survival rate due to lack of early diagnosis and effective therapies. Induction of the Fas-mediated apoptosis is a promising therapeutic target in this tumor. Studies from our group and others have indicated that Fas-expression correlates inversely with disease progression and that CaM-antagonists induce apoptosis in cholangiocarcinoma cells in a Fas related manner. Further, we reported a direct and dynamic interaction of CaM and Fas and that CaM is recruited into the Fas-stimulated death inducing signaling complex (DISC), suggesting a cross talk between Fas and CaM pathways. The studies presented in this dissertation were designed to characterize the role of CaM in Fas-induced signaling and identify potential therapies for cholangiocarcinoma. Fas-mediated apoptosis typically involves the recruitment of an adapter protein, FADD, caspase-8 and/or c-FLIP to form the DISC. Screening for the CaM binding proteins in the DISC, we demonstrated a Ca++-dependent direct interaction between CaM and FLIPL, but not the other DISC components, FADD, caspase-8 and FLIPS. Fas activation induced a Ca++ dependent increase in CaM-FLIP binding which was inhibited by CaM-antagonist, trifluoperazine (TFP), with concurrent inhibition of ERK phosphorylation and increased FLIP binding with ubiquitin. The CaM binding region was identified between aa 197-213 on FLIPL. Over expression of FLIPL decreased the sensitivity of cholangiocarcinoma cells to Fas and CaM-antagonist-induced apoptosis and increased their tumorigenicity in nude mice. Deletion of the CaM binding region from FLIPL restored the sensitivity of cholangiocarcinoma cells to Fas and CaM-antagonist-induced apoptosis and decreased their tumorigenicity in nude mice. The CaM-antagonist, tamoxifen (TMX), induced apoptosis in caspase dependent and independent manners with concurrent inhibition of pAKT and FLIP expression in cholangiocarcinoma cells. A combination of TMX and Gemcitabine, a currently used therapy for cholangiocarcinoma, induced more apoptosis than treatment with either agent alone. Thus the results of this dissertation support the concept that the CaM-FLIP binding is an important regulator of Fas- and CaM-antagonist-induced apoptosis and that it may provide a novel therapeutic target for cholangiocarcinoma. Further the CaMantagonist, TMX, may be used alone or in combination with Gemcitabine or other antineoplastic compounds as a therapy for cholangiocarcinoma.

vi, 159 p. : ill., digital, PDF file

Pathology

Joint Health Sciences

Calmodulin FLIP Fas Cholangiocarcinoma Tamoxifen

UNRESTRICTED

Advisors/Committee Members: McDonald, Jay, Bellis, Susan <br>, Fallon, Michael <br>, Mountz, John <br>, Ponnazhagan, Selvarangan<br>, Roth, Kevin.

Subjects/Keywords: Antigens, CD95  – metabolism <; br>; CASP8 and FADD-Like Apoptosis Regulating Protein  – metabolism <; br>; Calmodulin  – metabolism <; br>; Cholangiocarcinoma <; br>; Signal Transduction

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APA (6th Edition):

Pawar, P. S. (2008). Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,301

Chicago Manual of Style (16th Edition):

Pawar, Pritish Subhash. “Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma.” 2008. Doctoral Dissertation, University of Alabama – Birmingham. Accessed October 18, 2019. http://contentdm.mhsl.uab.edu/u?/etd,301.

MLA Handbook (7th Edition):

Pawar, Pritish Subhash. “Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma.” 2008. Web. 18 Oct 2019.

Vancouver:

Pawar PS. Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2008. [cited 2019 Oct 18]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,301.

Council of Science Editors:

Pawar PS. Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma. [Doctoral Dissertation]. University of Alabama – Birmingham; 2008. Available from: http://contentdm.mhsl.uab.edu/u?/etd,301

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