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.
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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)
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Chemical References |
- NPM1 protein, human
- Nuclear Proteins
- Tumor Suppressor Protein p53
- Nucleophosmin
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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)
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