Abstract
Here we identify a novel protein, named Parcs for pro-apoptotic protein required for cell survival, that is involved in both cell cycle progression and apoptosis. Parcs interacted with Apaf-1 by binding to the oligomerization domain of Apaf-1. Apaf-1-mediated activation of caspase-9 and caspase-3 was markedly decreased in a cytosolic fraction isolated from HeLa cells with reduced parcs expression. Interestingly, parcs deficiency blocked cell proliferation in non-tumorigenic cells but not in multiple tumor cell lines. In MCF-10A cells, parcs deficiency led to early G1 arrest. Conditional inactivation of parcs in genetically modified primary mouse embryonic fibroblasts using the Cre-LoxP system also resulted in the inhibition of cell proliferation. We conclude that Parcs may define a molecular checkpoint in the control of cell proliferation for normal cells that is lost in tumor cells.
Highlights
The formation of the apoptosome during apoptosis is regulated by multiple factors
We describe a novel protein that we termed Parcs for pro-apoptotic protein required for cell survival, which was isolated based on its ability to interact with the oligomerization domain of Apaf-1
We show that Parcs regulates the competency of Apaf-1 to form the apoptosome, as a cytosolic extract isolated from HeLa cells deficient in parcs expression was functionally defective in mediating caspase-9 activation in response to the addition of cytochrome c and dATP
Summary
The formation of the apoptosome during apoptosis is regulated by multiple factors. In an elegant series of biochemical studies, Wang and co-workers [4] demonstrated that cytochrome c, released from mitochondria during apoptosis, is a key factor in the formation of the apoptosome. We show that Parcs regulates the competency of Apaf-1 to form the apoptosome, as a cytosolic extract isolated from HeLa cells deficient in parcs expression was functionally defective in mediating caspase-9 activation in response to the addition of cytochrome c and dATP.
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