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

Abstract

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.

• Authors: June Li, Xiaoling Zhang, Daniel P Sejas, Qishen Pang
• Journal: Leukemia research (Leuk Res) Vol. 29 Issue 12 Pg. 1415-23 (Dec 2005) ISSN: 0145-2126 [Print] England
• PMID: 15964625 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NPM1 protein, human
• Nuclear Proteins
• Tumor Suppressor Protein p53
• Nucleophosmin

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line
• Cell Line, Tumor
• Gene Expression Regulation (drug effects, radiation effects)
• Humans
• Leukemia, Myeloid, Acute (pathology)
• Mice
• Mice, Knockout
• Myeloid Cells (cytology, drug effects)
• Nuclear Proteins (genetics, physiology)
• Nucleophosmin
• Radiation, Ionizing
• Stress, Physiological
• Transduction, Genetic
• Tumor Suppressor Protein p53 (deficiency, genetics)