Open AccessMisregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis
Author(s) -
Ajai J. Pulianmackal,
Kiriaki Kanakousaki,
Kerry Flegel,
Olga Grushko,
Ella Gourley,
Emily Rozich,
Laura Buttitta
Publication year - 2022
Publication title -
disease models and mechanisms
Language(s) - English
Resource type - Journals
eISSN - 1754-8411
pISSN - 1754-8403
DOI - 10.1242/dmm.049234
Subject(s) - nucleoporin , biology , carcinogenesis , chromosomal translocation , ectopic expression , cell cycle , microbiology and biotechnology , cancer research , fusion protein , loss function , genetics , apoptosis , nuclear protein , gene , transcription factor , phenotype , recombinant dna
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.