Cytoplasmic FANCA-FANCC Complex Interacts and Stabilizes the Cytoplasm-dislocalized Leukemic Nucleophosmin Protein (NPMc)
| Autor: | Jared Sipple, Qishen Pang, Jianjun Chen, Jie Li, Wei Du |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cytoplasm
congenital hereditary and neonatal diseases and abnormalities Fanconi anemia complementation group C Molecular Sequence Data Biology Biochemistry Ubiquitin Fanconi anemia Cell Line Tumor hemic and lymphatic diseases medicine Humans Nuclear protein Molecular Biology Nucleophosmin Leukemia Base Sequence Fanconi Anemia Complementation Group A Protein Protein Stability Fanconi Anemia Complementation Group C Protein Ubiquitination Nuclear Proteins nutritional and metabolic diseases Cell Biology medicine.disease Molecular biology FANCA Ubiquitin ligase Protein Transport Fanconi Anemia biology.protein Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 285:37436-37444 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.113209 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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