The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death

Mol Cell. 2005 Jun 10;18(6):637-50. doi: 10.1016/j.molcel.2005.05.010.


Tumor cells typically resist programmed cell death (apoptosis) induced by death receptors. Activated death receptors evoke Bax conformational change, cytochrome c release, and cell death. We report that the tumor suppressor gene RASSF1A is required for death receptor-induced Bax conformational change and apoptosis. TNFalpha or TRAIL stimulation induced recruitment of RASSF1A and MAP-1 to receptor complexes and promoted complex formation between RASSF1A and the BH3-like protein MAP-1. Normally, MAP-1 is inhibited by an intramolecular interaction. RASSF1A/MAP-1 binding relieved this inhibitory interaction, resulting in MAP-1 association with Bax. Deletion of the RASSF1A gene or short hairpin silencing of either RASSF1A or MAP-1 expression blocked MAP-1/Bax interaction, Bax conformational change and mitochondrial membrane insertion, cytochrome c release, and apoptosis in response to death receptors. Our findings identify RASSF1A and MAP-1 as important components between death receptors and the apoptotic machinery and reveal a potential link between tumor suppression and death receptor signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Breast Neoplasms
  • Cell Death
  • Cell Line, Tumor
  • Cell Survival / physiology*
  • Cytochromes c / analysis
  • Female
  • Gene Deletion
  • Humans
  • Intracellular Membranes / physiology
  • Mitochondria / physiology
  • Protein Conformation
  • Proto-Oncogene Proteins c-bcl-2 / chemistry*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • bcl-2-Associated X Protein


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BAX protein, human
  • MOAP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • Cytochromes c