Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis

Nucleoporin 98KD (Nup98) is a promiscuous translocation partner in hematological malignancies. Most disease models of Nup98 translocations involve ectopic expression of the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is the loss of one co...

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Bibliographic Details
Published in:Disease models & mechanisms 2022-03, Vol.15 (3)
Main Authors: Pulianmackal, Ajai J, Kanakousaki, Kiriaki, Flegel, Kerry, Grushko, Olga G, Gourley, Ella, Rozich, Emily, Buttitta, Laura A
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cancer
Cell cycle
Cell Transformation, Neoplastic
compensatory proliferation
Cooperation
Drosophila as a Disease Model
Drosophila melanogaster - genetics
Drosophila melanogaster - metabolism
drosophila wing
Ectopic expression
Fusion protein
Gene expression
Hematological diseases
Insects
jnk signaling
Malignancy
mRNA
Mutation
nuclear pore complex
Nuclear Pore Complex Proteins - genetics
Nucleoporins
Protein biosynthesis
Proteins
ribosome biogenesis
RNA, Messenger
Tumorigenesis
Wounding
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Summary:Nucleoporin 98KD (Nup98) is a promiscuous translocation partner in hematological malignancies. Most disease models of Nup98 translocations involve ectopic expression of the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is the loss of one copy of normal Nup98 in addition to the loss of Nup96 - a second Nucleoporin encoded within the same mRNA and reading frame as Nup98 - in translocations. Nup98 and Nup96 are also mutated in a number of other cancers, suggesting that their disruption is not limited to blood cancers. We found that reducing Nup98-96 function in Drosophila melanogaster (in which the Nup98-96 shared mRNA and reading frame is conserved) de-regulates the cell cycle. We found evidence of overproliferation in tissues with reduced Nup98-96, counteracted by elevated apoptosis and aberrant signaling associated with chronic wounding. Reducing Nup98-96 function led to defects in protein synthesis that triggered JNK signaling and contributed to hallmarks of tumorigenesis when apoptosis was inhibited. We suggest that partial loss of Nup98-96 function in translocations could de-regulate protein synthesis, leading to signaling that cooperates with other mutations to promote tumorigenesis.
ISSN:1754-8403
1754-8411
1754-8411
DOI:10.1242/dmm.049234