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.
Li
June
J
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Zhang
Xiaoling
X
Sejas
Daniel P
DP
Pang
Qishen
Q
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000090243:Nucleophosmin; D011839:Radiation, Ionizing; D013312:Stress, Physiological; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin