ABSTRACT

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.

Transgenic mice have been used to address the issue of the oncogenic potential of mutant guanine nucleotide stimulatory factor (G.) a subunit in the thyroid gland. (GO, respectively (1,2). G proteins are heterotrimeric complexes composed of a, (3, and y subunits. The a subunit cycles between a GTP-bound active monomeric form and an inactive GDP-bound form. Transition from inactive to active form results from the exchange of GDP for GTP induced by the receptor, whereas transition from active to inactive form results from hydrolysis of the bound GTP by the GTPase activity of the a subunit (3, 4).