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M511710200v1
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Papers In Press, published online ahead of print February 8, 2006
J. Biol. Chem, 10.1074/jbc.M511710200
Submitted on October 31, 2005
Revised on January 27, 2006
Accepted on February 8, 2006

Lipid phosphate phosphatase-2 activity regulates S-phase entry of the cell cycle in rat2 fibroblasts

Katherine E. Morris, Luis M. Schang, and David N. Brindley

Biochemistry Dept., University of Alberta, Edmonton, Alberta T6G 2S2

Corresponding Author: david.brindley{at}ualberta.ca

Lipid phosphates are potent mediators of cell signaling and control processes including development, cell migration and division, blood vessel formation, wound repair, and tumor progression. Lipid phosphate phosphatases (LPPs) regulate the dephosphorylation of lipid phosphates, thus modulating their signals and producing new bioactive compounds both at the cell surface and in intracellular compartments. Knock down of endogenous LPP2 in fibroblasts delayed cyclin A accumulation and entry into S-phase of the cell cycle. Conversely, over-expression of LPP2, but not a catalytically inactive mutant, caused premature S-phase entry, accompanied by premature cyclin A accumulation. At high passage, many LPP2 over-expressing cells arrested in G2/M and the rate of proliferation declined severely. This was accompanied by changes in proteins and lipids characteristic of senescence. Additionally, arrested LPP2 cells contained decreased lysophosphatidate concentrations and increased ceramide. These effects of LPP2 activity were not reproduced by over-expression or knock down of LPP1 or LPP3. This work identifies a novel and specific role for LPP2 activity and bioactive lipids in regulating cell cycle progression.


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