Loss of FADD protein expression results in a biased Fas-signaling pathway and correlates with the development of tumoral status in thyroid follicular cells

Oncogene. 2003 May 8;22(18):2795-804. doi: 10.1038/sj.onc.1206399.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis
  • Base Sequence
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Caspases
  • Cell Line
  • DNA Primers
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Gene Expression Regulation, Neoplastic / physiology*
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Thyroid Gland / physiopathology
  • Thyroid Neoplasms / genetics*
  • fas Receptor / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Primers
  • Fadd protein, mouse
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • RNA, Messenger
  • fas Receptor
  • Caspases