Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 43, Pages 16834-16839Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0708189104
Keywords
acetylated p53; inositol signaling; nuclear translocation
Categories
Funding
- NHLBI NIH HHS [R01 HL016634, HL 16634] Funding Source: Medline
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A recently discovered phosphaticlylinositol monophosphate, phosphaticlylinositol 5-phosphate (Ptdlns-5-13), 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 phosphaticlylinositol 4,5-bisphosphate (Ptdlns-45-PA, forming Ptdlns-5-P in vitro, can increase the cellular levels of Ptdlns-5-P. When HeLa cells were treated with the I 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 Ptdlns-5-P and thereby p53-dependent apoptosis.
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