Role of nucleophosmin in normal hematopoiesis and leukemia
Although most solid tumors contain inactivation of the tumor suppressor p53 by various genetic alterations, much less genetic mutations have been detected in either p53 or its downstream effector genes in hematological malignancies. We are interested in understanding how these cancers develop in the presence of a major tumor suppressor. It is believed that hematological tumors have developed alternative mechanisms of inhibition of p53 activity, leading to bypassing the requirement for p53 mutations. We and others have recently identified a novel cellular inhibitor of p53, nucleophosmin (NPM) that is frequently overexpressed in a variety of human cancers including leukemia evolved from Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and leukemic transformation. We demonstrated that NPM inhibits p53 activity and protects cells from stress-induced apoptosis. We hypothesize that inhibition of p53 is one mechanism by which NPM promotes cell proliferation and suppresses apoptosis and that leukemic transformation in FA and other related cancer-prone bone marrow diseases may require increased expression of NPM to keep p53 activity in check and to maintain cell survival and proliferation. The long-term goals of our study are to utilize FA as an experimental system to examine the role of NPM in the selection and progression of human cancers, particularly in the context of p53 regulation.
Related Publications
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Li J, Zhang X, Sejas DP, Pang Q. (2005) Negative regulation of p53 by nucleophosmin antogonizes stress-induced apoptosis in human normal and malignant hematopoietic cells. Leuk Res. 29:1415-1423.
Li J, Sejas DP, Rani R, Korestsky T, Bagby GC, Pang Q. (2006) Nucleophosmin regulates cell cycle progression and stress response in hematopoietic stem/progentitor cells. J. Biol. Chem 281: 16536-16545.
Li, J.; Zhang, X.; Sejas, D.P.; Bagby, G.C.; and Pang, Q (2004) Hypoxia-induced nucleophosimn protects cell death through inhibition of p53. J. Biol. Chem 279: 41275-41279.
For further information regarding Dr. Pang's research, please contact Dr. Qishen Pang at 513-636-1152. For additional information about the Division of Experimental Hematology, please contact Dr. David Williams at 513-636-0364. The Division of Experimental Hematology can be found in Room 6529 of Location R (Research Foundation Building).
