Details

Autor(en) / Beteiligte

• Huang, XiaoDong
• Masselli, Anja
• Frisch, Steven M.
• Hunton, Irina C.
• Jiang, Yong
• Wang, Jean Y.J.

Titel

Blockade of Tumor Necrosis Factor-induced Bid Cleavage by Caspase-resistant Rb

Ist Teil von

• The Journal of biological chemistry, 2007-10, Vol.282 (40), p.29401-29413

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2007

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Tumor necrosis factor-α (TNF) activates caspase-8 to cleave effector caspases or Bid, resulting in type-1 or type-2 apoptosis, respectively. We show here that TNF also induces caspase-8-dependent C-terminal cleavage of the retinoblastoma protein (Rb). Interestingly, fibroblasts from RbMI/MI mice, in which the C-terminal caspase cleavage site is mutated, exhibit a defect in Bid cleavage despite caspase-8 activation. Recent results suggest that TNF receptor endocytosis is required for the activation of caspase-8. Consistent with this notion, inhibition of V-ATPase, which plays an essential role in acidification and degradation of endosomes, specifically restores Bid cleavage in RbMI/MI cells. Inhibition of V-ATPase sensitizes RbMI/MI but not wild-type fibroblasts to TNF-induced apoptosis and stimulates inflammation-associated colonic apoptosis in RbMI/MI but not wild-type mice. These results suggest that Rb cleavage is required for Bid cleavage in TNF-induced type-2 apoptosis, and this requirement can be supplanted by the inhibition of V-ATPase.