Evidence for a Function of Death-Receptor-Related, Death-Domain-Containing Proteins in Anoikis

Curr Biol. 1999 Sep 23;9(18):1047-9. doi: 10.1016/s0960-9822(99)80455-2.

Abstract

Normal epithelial cells undergo apoptosis if integrinmediated matrix contacts are lost, in a process termed 'anoikis'. Anoikis prevents shed epithelial cells from colonizing elsewhere, and is thus essential for maintaining appropriate tissue organisation. Aberrant oncogenes or tumor suppressor genes can cause resistance to anoikis, thereby contributing substantially to malignancy. Apoptosis is mediated by a well-ordered signaling cascade, which involves activation of intracellular proteases known as caspases. However, the mechanism by which the caspase cascade is initiated following cell-matrix detachment is unknown. We have hypothesized that death receptor activation might be involved in anoikis. To test this hypothesis, we developed a transient assay for anoikis and used it to assay the effects of proteins that block the function of domains found within death receptors known as death domains. In this assay, silencer of death domains (SODD) and dominant-negative FAS-associated death domain protein (FADD) efficiently inhibited anoikis in Madin-Darby canine kidney (MDCK) cells. The protective activity of SODD required its BAG domain, which interacts with the heat shock proteins hsp70 and hsc70, and inhibits the chaperone activity of the latter. Both caspase 8, which physically associates with death receptors, and cleavage of the caspase-8 substrate BID, were activated by cell-matrix detachment. These findings indicate a role for death receptors or proteins with related death domains in triggering anoikis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Arabidopsis Proteins*
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Caspase 8
  • Caspase 9
  • Caspases / physiology*
  • Cell Adhesion / physiology*
  • Cell Line
  • Dogs
  • Enzyme Activation
  • Epithelial Cells / cytology
  • Extracellular Matrix / physiology
  • Fatty Acid Desaturases / chemistry
  • Fatty Acid Desaturases / physiology*
  • HSC70 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins / metabolism
  • Kidney
  • Models, Biological
  • Peptide Fragments / metabolism
  • Protein Structure, Tertiary
  • Signal Transduction

Substances

  • Arabidopsis Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins
  • HSC70 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Peptide Fragments
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Caspase 8
  • Caspase 9
  • Caspases