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NUP98 fusion oncoproteins interact with the APC/CCdc20as a pseudosubstrate and prevent mitotic checkpoint complex binding
- Source :
- Cell Cycle. 15:2275-2287
- Publication Year :
- 2016
- Publisher :
- Informa UK Limited, 2016.
-
Abstract
- NUP98 is a recurrent partner gene in translocations causing acute myeloid leukemias and myelodisplastic syndrome. The expression of NUP98 fusion oncoproteins has been shown to induce mitotic spindle defects and chromosome missegregation, which correlate with the capability of NUP98 fusions to cause mitotic checkpoint attenuation. We show that NUP98 oncoproteins physically interact with the APC/C(Cdc20) in the absence of the NUP98 partner protein RAE1, and prevent the binding of the mitotic checkpoint complex to the APC/C(Cdc20). NUP98 oncoproteins require the GLEBS-like domain present in their NUP98 moiety to bind the APC/C(Cdc20). We found that NUP98 wild-type is a substrate of APC/C(Cdc20) prior to mitotic entry, and that its binding to APC/C(Cdc20) is controlled via phosphorylation of a PEST sequence located within its C-terminal portion. We identify S606, within the PEST sequence, as a key target site, whose phosphorylation modulates the capability of NUP98 to interact with APC/C(Cdc20). We finally provide evidence for an involvement of the peptidyl-prolyl isomerase PIN1 in modulating the possible conformational changes within NUP98 that lead to its dissociation from the APC/C(Cdc20) during mitosis. Our results provide novel insight into the mechanisms underlying the aberrant capability of NUP98 oncoproteins to interact with APC/C(Cdc20) and to interfere with its function.
- Subjects :
- 0301 basic medicine
Oncogene Proteins, Fusion
oncogenes
Cdc20 Proteins
Mitosis
CDC20
acute myeloid leukemia
Biology
Substrate Specificity
03 medical and health sciences
PEST sequence
0302 clinical medicine
nucleoporins
Protein Domains
Humans
Molecular Biology
Protein Stability
Mitotic checkpoint complex
Cell Biology
Cell cycle
anaphase promoting complex
Spindle apparatus
Cell biology
NIMA-Interacting Peptidylprolyl Isomerase
Nuclear Pore Complex Proteins
HEK293 Cells
030104 developmental biology
mitotic checkpoint
030220 oncology & carcinogenesis
Mad2 Proteins
Cancer research
PIN1
cell cycle
myelodisplastic syndrome
NUP98
Developmental Biology
M Phase Cell Cycle Checkpoints
Anaphase-promoting complex
Reports
HeLa Cells
Protein Binding
Subjects
Details
- ISSN :
- 15514005 and 15384101
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Cell Cycle
- Accession number :
- edsair.doi.dedup.....586d72d75a279bc1243c90ad39a5c75e
- Full Text :
- https://doi.org/10.1080/15384101.2016.1172156