title: Cleavage of phospholipase D1 by caspase promotes apoptosis via modulation of the p53-dependent cell death pathway.
abstract: The enzymatic activity of phospholipase D (PLD) is known to be essential for cell survival and protection from apoptosis. However, the mechanisms regulating PLD activity during apoptosis remain unknown. Here we report that cleavage of PLD1 by caspases facilitates p53-mediated apoptosis. Cleavage of PLD1 into an N-terminal fragment (NF-PLD1) and a C-terminal fragment at the amino-acid sequence, DDVD(545), led to a reduction in PLD1 activity. However, a caspase-resistant mutant form of PLD1 retained significant levels of enzymatic activity and apoptotic function as compared to wild-type PLD1. Exogenous NF-PLD1 expression induced apoptosis through a dominant-negative effect on the activity of endogenous PLD1. During apoptosis, a small fraction of PLD1 is cleaved by caspases in a p53-independent manner and NF-PLD1 amplifies apoptotic signaling through inhibition of the remaining PLD1 activity. As PLD1 suppresses the ATM-Chk2-p53 pathway, elimination of PLD1 activity through NF-PLD1 or si-RNA against PLD1 increases apoptosis in a p53-dependent manner. Taken together, our results reveal that cleavage of PLD1 by caspases promotes apoptosis via modulation of the p53-dependent cell death pathway.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Korea.
authors.forename: Y H
authors.initials: YH
authors.lastname: Jang
authors.forename: S
authors.initials: S
authors.lastname: Namkoong
authors.forename: Y M
authors.initials: YM
authors.lastname: Kim
authors.forename: S-J
authors.initials: SJ
authors.lastname: Lee
authors.forename: B-J
authors.initials: BJ
authors.lastname: Park
authors.forename: D S
authors.initials: DS
authors.lastname: Min
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010739:Phospholipase D / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D010739:Phospholipase D; C106801:phospholipase D1; D020169:Caspases