Loss of FADD protein expression results in a biased Fas-signaling pathway and correlates with the development of tumoral status in thyroid follicular cells.
Downregulation of proapoptotic molecules like Fas or caspase 8, or upregulation of antiapoptotic molecules like FLICE inhibitory protein has been suggested to be a regulatory mechanism set up by tumor cells to block the death signal received via death receptors. In an in-depth study of the Fas/FasL-signaling pathway in thyroid tumor development, we have demonstrated that tumor cells specifically downregulate the multideath receptor adapter Fas-associated death domain (FADD). The regulation of FADD expression occurred only at the protein level. Furthermore, in the absence of FADD, Fas-signaling resulted in accelerated growth of thyrocytes. Since thyrocytes also acquired FasL expression during tumor development, the absence of FADD protein could lead to greater resistance to numerous death receptor-mediated apoptosis, stimulation of their own proliferation through Fas/FasL interaction, and the capacity to counter-attack the infiltrating lymphocytes.
Département d'Immunologie, Institut Cochin, INSERM U567, CNRS UMR 8104, IFR 116, Université René Descartes, 27 rue du fbg St-Jacques, 75014 Paris, France.
Léa
L
Tourneur
Sylvie
S
Mistou
Francine-Marie
FM
Michiels
Valérie
V
Devauchelle
Laurent
L
Renia
Jean
J
Feunteun
Gilles
G
Chiocchia
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D020169:Caspases; D002460:Cell Line; D017931:DNA Primers; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013961:Thyroid Gland / Q000503:physiopathology; D013964:Thyroid Neoplasms / Q000235:genetics*; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D020169:Caspases