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

Wei Du, Jie Li, Jared Sipple, Jianjun Chen, Qishen Pang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37436-37444
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number48
DOIs
StatePublished - Nov 26 2010

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Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.

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