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

Abstract

The 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 96 are also mutated in a number of other cancers, suggesting their disruption is not limited to blood cancers. We found that reducing Nup98-96 function in Drosophila melanogaster (where the Nup98-96 shared mRNA and reading frame is conserved) de-regulates the cell cycle. We find evidence of over-proliferation in tissues with reduced Nup98-96, counteracted by elevated apoptosis and aberrant signaling associated with chronic wounding. Reducing Nup98-96 function leads to defects in protein synthesis that trigger JNK signaling and contributes to hallmarks of tumorigenesis when apoptosis is inhibited. We suggest partial loss of Nup98-96 function in translocations could de-regulate protein synthesis leading to signaling that cooperates with other mutations to promote tumorigenesis.

Nuclear pore complexes undergo Nup221 exchange during blood stage asexual replication of Plasmodium parasites.

“…With the identification of numerous Nups in the Plasmodium genome (Kehrer, Kuss et al 2018, Ambekar Sushma, Beck Josh et al 2022), and improved tools for visualizing NPCs, we are now poised to investigate the individual functions of Nups. While the exact roles of specific Nups in the Plasmodium parasites remains unknown, studies in other organisms have illuminated the involvement of FG Nups in various cellular processes such as protein synthesis (Pulianmackal, Kanakousaki et al 2022), NPC localization and composition (Wu, Kasper et al 2001, Ferreira, Stear et al 2017), as well as RNA transport (Powers, Forbes et al 1997, Courjol, Mouveaux et al 2017). While no studies of specific FG Nup function have been conducted in Plasmodium parasites, deletions of Nup138 and Nup221 in genome wide screens and individual knock-out atempts have shown all Nups to be essential (Gomes, Bushell et al 2015, Bushell, Gomes et al 2017, Zhang, Wang et al 2018).…”

“…With the iden�fica�on of numerous Nups in the Plasmodium genome [15,17], and improved tools for visualizing NPCs, we are now poised to inves�gate the individual func�ons of Nups. While the exact roles of specific Nups in the Plasmodium parasites remains unknown, studies in other organisms have illuminated the involvement of FG Nups in various cellular processes such as protein synthesis [44], NPC localiza�on and composi�on [45,46], as well as RNA transport [6,47]. While no studies of specific FG Nup func�on have been conducted in Plasmodium parasites, dele�ons of Nup138 and Nup221 in genome wide screens and individual knock-out atempts have shown all Nups to be essen�al [48][49][50].…”

“…With the iden�fica�on of numerous Nups in the Plasmodium genome (Kehrer, Kuss et al 2018, Ambekar Sushma, Beck Josh et al 2022, and improved tools for visualizing NPCs, we are now poised to inves�gate the individual func�ons of Nups. While the exact roles of specific Nups in the Plasmodium parasites remains unknown, studies in other organisms have illuminated the involvement of FG Nups in various cellular processes such as protein synthesis (Pulianmackal, Kanakousaki et al 2022), NPC localiza�on and composi�on (Wu, Kasper et al 2001, Ferreira, Stear et al 2017, as well as RNA transport (Powers, Forbes et al 1997, Courjol, Mouveaux et al 2017.…”

Germline NUP98 Variants in Two Siblings with a Rothmund–Thomson-Like Spectrum: Protein Functional Changes Predicted by Molecular Modeling

“…In keeping with the most reported NUP-caused human diseases [ 3 ], NUP98 nucleoporopathy shows an autosomal recessive inheritance, which might suggest a loss-of-function mutation mechanism. However, NUP98 belongs to the category of “goldilockers” genes, whose up or down misregulation disrupts normal function, accounting for the “paradoxical” result of cell-cycle exit with defects in protein synthesis that promote hallmarks of tumorigenesis observed in Drosophila by both Nup98 reduction and overexpression [ 35 ].…”

HER2 as a potential therapeutic target on quiescent prostate cancer cells

“…PC3 integrated with cell cycle reporters : To develop a method to identify dormant cells, we transduced a human prostate cancer cell line, PC-3 with lentiviruses containing the fluorescent ubiquitination-based cell cycle reporters [ 12 , 37 ]. Both of the CDT1-mCherry reporter (pRetroX-mCherry-hCdt1 (30-120), Takara) and the p27 cyclin-dependent kinase inhibitor protein -Venus reporter (pMXs-IP-mVenus-p27, kindly provided to T. Oki, RIKEN) were packaged into lentivirus at the University of Michigan Vector Core Facility.…”