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J Biol Chem. 2010 Nov 26;285(48):37436-44. doi: 10.1074/jbc.M110.113209. Epub 2010 Sep 23.

Cytoplasmic FANCA-FANCC complex interacts and stabilizes the cytoplasm-dislocalized leukemic nucleophosmin protein (NPMc).

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1
Division of Experimental Hematology and Cancer Biology, the Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Abstract

Eight of the Fanconi anemia (FA) proteins form a core complex that activates the FA pathway. Some core complex components also form subcomplexes for yet-to-be-elucidated functions. Here, we have analyzed the interaction between a cytoplasmic FA subcomplex and the leukemic nucleophosmin (NPMc). Exogenous NPMc was degraded rapidly in FA acute myeloid leukemia bone marrow cells. Knockdown of FANCA or FANCC in leukemic OCI/AML3 cells induced rapid degradation of endogenous NPMc. NPMc degradation was mediated by the ubiquitin-proteasome pathway involving the IBR-type RING-finger E3 ubiquitin ligase IBRDC2, and genetic correction of FA-A or FA-C lymphoblasts prevented NPMc ubiquitination. Moreover, cytoplasmic FANCA and FANCC formed a cytoplasmic complex and interacted with NPMc. Using a patient-derived FANCC mutant and a nuclearized FANCC, we demonstrated that the cytoplasmic FANCA-FANCC complex was essential for NPMc stability. Finally, depletion of FANCA and FANCC in NPMc-positive leukemic cells significantly increased inflammation and chemoresistance through NF-κB activation. Our findings not only reveal the molecular mechanism involving cytoplasmic retention of NPMc but also suggest cytoplasmic function of FANCA and FANCC in NPMc-related leukemogenesis.

PMID:
20864535
PMCID:
PMC2988349
DOI:
10.1074/jbc.M110.113209
[Indexed for MEDLINE]
Free PMC Article
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