Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16834-9. doi: 10.1073/pnas.0708189104. Epub 2007 Oct 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Apoptosis*
  • Cell Line
  • Cell Nucleus / enzymology
  • HeLa Cells
  • Homeodomain Proteins / metabolism
  • Humans
  • Models, Biological
  • Oxidative Stress*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Transport
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Thermodynamics
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism


  • Homeodomain Proteins
  • ING2 protein, human
  • Phosphatidylinositol Phosphates
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • phosphatidylinositol 5-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Phosphoric Monoester Hydrolases
  • phosphoinositide 5-phosphatase