Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis.
A recently discovered phosphatidylinositol monophosphate, phosphatidylinositol 5-phosphate (PtdIns-5-P), plays an important role in nuclear signaling by influencing p53-dependent apoptosis. It interacts with a plant homeodomain finger of inhibitor of growth protein-2, causing an increase in the acetylation and stability of p53. Here we show that type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase (type I 4-phosphatase), an enzyme that dephosphorylates phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P(2)), forming PtdIns-5-P in vitro, can increase the cellular levels of PtdIns-5-P. When HeLa cells were treated with the DNA-damaging agents etoposide or doxorubicin, type I 4-phosphatase translocated to the nucleus and nuclear levels of PtdIns-5-P increased. This action resulted in increased p53 acetylation, which stabilized p53, leading to increased apoptosis. Overexpression of type I 4-phosphatase increased apoptosis, whereas RNAi of the enzyme diminished it. The half-life of p53 was shortened from 7 h to 1.8 h upon RNAi of type I 4-phosphatase. This enzyme therefore controls nuclear levels of PtdIns-5-P and thereby p53-dependent apoptosis.
Zou
Jun
J
Division of Hematology-Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Marjanovic
Jasna
J
Kisseleva
Marina V
MV
Wilson
Monita
M
Majerus
Philip W
PW
D000107:Acetylation; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D018384:Oxidative Stress; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099182:Phosphoinositide 5-Phosphatases
D018398:Homeodomain Proteins; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000099182:Phosphoinositide 5-Phosphatases; C444654:ING2 protein, human; C113567:phosphatidylinositol 5-phosphate