Negative regulation of p53 by nucleophosmin antagonizes stress-induced apoptosis in human normal and malignant hematopoietic cells.

Nucleophosmin (NPM) is a multifunctional protein frequently overexpressed in actively proliferating cells including tumor and stem cells. Here we show that NPM acts as a cellular p53 negative regulator to protect normal and malignant hematopoietic cells from stress-induced apoptosis. Overexpression of NPM suppresses stress-induced apoptosis in the granulocyte-macrophage colony-stimulating factor ...
(GM-CSF)-dependent myeloid cell line MO7e and the lymphoblast HSC536 cells derived from a Fanconi anemia (FA) patient. In addition, suppression of NPM expression by small interfering RNA targeting NPM in normal lymphoblasts and FA-associated acute myelogenous leukemia (AML) cells increases DNA damage-induced apoptosis. However, overexpression of the mutant NPMDeltaC, which lacks the p53-interacting domain, fails to confer cellular resistance to stress-induced apoptosis, suggesting that NPM protects cells from apoptotic cell death through a mechanism involving p53. Indeed, using the genetically matched p53 wild-type (WT) and null mouse bone marrow (BM) cells, we demonstrate that forced expression of NPM protects against ionizing irradiation (IR)-induced apoptosis of WT but not p53-null BM cells. Moreover, NPM inhibits IR-induced p53 transactivation, and interacts with p53 in hematopoietic cells. Thus, these results indicate an important role for NPM in regulation of p53-dependent apoptotic response and implicate a potential effect in cancer therapy.
Mesh Terms:
Animals, Apoptosis, Cell Line, Cell Line, Tumor, Gene Expression Regulation, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Knockout, Myeloid Cells, Nuclear Proteins, Radiation, Ionizing, Stress, Physiological, Transduction, Genetic, Tumor Suppressor Protein p53
Leuk. Res.
Date: Dec. 01, 2005
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