Role of GADD34 (Growth Arrest and DNA Damage-Inducible Protein) in Regulating Apoptosis, Proliferation, and Protein Synthesis in Human Breast Cancer Cells

摘要

The proto-oncogene c-myc has been widely implicated in human cancer. One of the major cellular targets of c-myc is the stress-induced gene GADD34. GADD34 is a potent apoptotic-inducer, but c-myc expression potently inhibits GADD34 expression, indicating that GADD34 may be an important target of c-myc-mediated oncogenesis. 3ADD34 is a scaffolding protein that interacts with several proteins including Protein Phosphatase 1 (PP1) and a PP1 inhibitor, Inhibitor-1 (I-1) sub 3. GADD34 binds and targets PP1 to the eukaryotic inhibitor factor 2 alpha (eIF2 alpha) and promotes its dephosphorylation. The reversible phosphorylation of eIF2 alpha is a critical step in the control of translation by stress signaling and is the target of several kinases. Interestingly, the anti-cancer drug methylselenocysteine (MSC or Avemar) both promotes apoptosis and GADD34 expression in human cancer cells sub 4. Another drug, salubrinal, inhibits the GADD34-PP1 complex, and inhibits apoptosis in mammalian cells sub 5. This indicates that GADD34 could prove to be an important target for anticancer therapies.