| RRC ID |
15309
|
| 著者 |
Funasaka T, Nakano H, Wu Y, Hashizume C, Gu L, Nakamura T, Wang W, Zhou P, Moore MA, Sato H, Wong RW.
|
| タイトル |
RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis.
|
| ジャーナル |
Cell Cycle
|
| Abstract |
Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis. We previously showed that RAE1 depletion caused aneuploidy, which enhanced tumorigenesis. We speculated that RAE1 may also be directly involved in NUP98 fusion-mediated leukemogenesis. We show here that RNA interference (RNAi)-mediated knockdown of NUP98 caused severe chromosome segregation defects and disrupted RAE1 but not HDAC1 expression and localization. Next, we performed rescue experiments to confirm that the RAE1-NUP98 complex orchestrates proper chromosome segregation. Interestingly, we found diverse behaviors of NUP98 and the leukemogenic fusion protein NUP98-HOXA9 throughout the cell cycle. Strikingly, in NUP98-HOXA9-transfected cells, RAE1 protein were reduced and mis-localized. Our cellular interpretations were further confirmed by NUP98-HOXA9 transgenic mice and the NUP98-HOXA9 AML patient. These data suggest that RAE1 orchestrates NUP98-mediated leukemogenesis and raise the possibility that targeting this negative feedback loop may provide a new strategy for the therapy of aggressive leukemias.
|
| 巻・号 |
10(9)
|
| ページ |
1456-67
|
| 公開日 |
2011-5-1
|
| DOI |
10.4161/cc.10.9.15494
|
| PII |
15494
|
| PMID |
21467841
|
| MeSH |
Adult
Animals
Chromosome Segregation / genetics
Female
Gene Expression Regulation, Leukemic* / physiology
HEK293 Cells
HeLa Cells
Homeodomain Proteins / genetics
Homeodomain Proteins / physiology*
Humans
K562 Cells
Leukemia, Myeloid, Acute / etiology
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / pathology*
Mice
Mice, Transgenic
Middle Aged
Nuclear Matrix-Associated Proteins / genetics
Nuclear Matrix-Associated Proteins / physiology*
Nuclear Pore Complex Proteins / genetics
Nuclear Pore Complex Proteins / physiology*
Nucleocytoplasmic Transport Proteins / genetics
Nucleocytoplasmic Transport Proteins / physiology*
Protein Structure, Tertiary / genetics
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
|
| IF |
3.699
|
| 引用数 |
25
|
|
WOS 分野
|
CELL BIOLOGY
|
| リソース情報 |
| 実験動物マウス |
RBRC01188 |
