The Role of Capase-8 in Breast Carcinoma Cells
Annual summary rept. 28 Mar 2003-27 Mar 2006
CHICAGO UNIV IL
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Breast cancer is the second leading cause of cancer related death for women in the United States. Interestingly, breast cancer cells often highly express the Fas CD95APO-1 receptor, which is well established as an activator of apoptosis programmed cell death upon ligand binding. Fas induces apoptosis by recruiting proteins that form the death inducing signaling complex DISC. Type I cells form large amounts of the DISC and internalize Fas, whereas in Type II cells Fas does not internalize and the DISC is almost undetectable. Additionally the Fas receptor has recently been shown to activate the nonapoptotic NF- B and MAP kinase pathways upon receptor stimulation in either Type I or Type II cells. We can now demonstrate that in Type I cells the recruitment of DISC largely occurs after the receptor has moved into an endosomal compartment and blocking internalization prevents formation of the DISC. Receptor internalization is not required for NF- B and Erk12 activation. Consequently dimerization of Fas complexes does not induce internalization of Fas nor apoptosis but is sufficient to induce nonapoptotic-signaling pathways and increases motility and invasiveness of tumor cells. Monomeric Fas binding in not sufficient to activate nonapoptotic playways. Furthermore, we can demonstrate SNARKs role as a nonapoptotic kinase and promoter of motility and invasion.
- Medicine and Medical Research