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Cell. 2009 Jul 23;138(2):377-88. doi: 10.1016/j.cell.2009.05.022.

The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis.

Author information

1
Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.

Erratum in

  • Cell. 2009 Sep 4;138(5):1032.

Abstract

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.

Comment in

PMID:
19632185
PMCID:
PMC2774252
DOI:
10.1016/j.cell.2009.05.022
[Indexed for MEDLINE]
Free PMC Article

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