The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis.
Prostate apoptosis response-4 (Par-4) is a proapoptotic protein with intracellular functions in the cytoplasm and nucleus. Unexpectedly, we noted Par-4 protein is spontaneously secreted by normal and cancer cells in culture, and by Par-4 transgenic mice that are resistant to spontaneous tumors. Short exposure to endoplasmic reticulum (ER) stress-inducing agents ... further increased cellular secretion of Par-4 by a brefeldin A-sensitive pathway. Secretion occurred independently of caspase activation and apoptosis. Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells. The interaction of extracellular Par-4 and cell surface GRP78 led to apoptosis via ER stress and activation of the FADD/caspase-8/caspase-3 pathway. Moreover, apoptosis inducible by TRAIL, which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling via cell surface GRP78. Thus, Par-4 activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.
Mesh Terms:
Animals, Apoptosis, Brefeldin A, Cell Line, Cell Line, Tumor, Endoplasmic Reticulum, Heat-Shock Proteins, Humans, Mice, Mice, Transgenic, Protein Structure, Tertiary, Protein Transport, Receptors, Thrombin
Animals, Apoptosis, Brefeldin A, Cell Line, Cell Line, Tumor, Endoplasmic Reticulum, Heat-Shock Proteins, Humans, Mice, Mice, Transgenic, Protein Structure, Tertiary, Protein Transport, Receptors, Thrombin
Cell
Date: Jul. 23, 2009
PubMed ID: 19632185
View in: Pubmed Google Scholar
Download Curated Data For This Publication
126827
Switch View:
- Interactions 3