A novel antiapoptotic mechanism based on interference of Fas signaling by CD44 variant isoforms.
There is growing evidence that one of the central common characteristics of tumor and inflammatory cells is their resistance to programmed cell death. This feature results in the accumulation of harmful cells, which are mostly refractory to Fas (FAS, APO-1)-mediated apoptosis. A molecule found on these cells is the transmembrane receptor CD44 with its variant isoforms (CD44v). The establishment of transfectants expressing different CD44v isoforms allowed us to demonstrate that the CD44v6 and CD44v9 isoforms exhibit an antiapoptotic effect and can block Fas-mediated apoptosis. Moreover, we observed that CD44v6 and CD44v9 colocalize and interact with Fas. Importantly, an anti-CD44v6 antibody can abolish the antiapoptotic effect of CD44v6. These results are the first to show that CD44v isoforms interfere with Fas signaling. Our findings improve the understanding of the pathogenesis of cancer and autoimmunity and open new strategies to treat such disorders.
Mielgo
A
A
1Institute of Medical Microbiology, Department of Clinical and Biological Sciences, University of Basel, CH 4003 Basel, Switzerland.
van Driel
M
M
Bloem
A
A
Landmann
L
L
Günthert
U
U
D017209:Apoptosis; D002460:Cell Line; D006023:Glycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000378:metabolism*; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000032:analysis / Q000378:metabolism*
C473647:CD44S antigen; C112697:CD44v6 antigen; C448906:CD44v9 antigen; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D019014:fas Receptor