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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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-03-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/15/3/dmm049234 |
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| author | Ajai J. Pulianmackal Kiriaki Kanakousaki Kerry Flegel Olga G. Grushko Ella Gourley Emily Rozich Laura A. Buttitta |
| author_facet | Ajai J. Pulianmackal Kiriaki Kanakousaki Kerry Flegel Olga G. Grushko Ella Gourley Emily Rozich Laura A. Buttitta |
| author_sort | Ajai J. Pulianmackal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T18:05:27Z |
| format | Article |
| id | doaj.art-9fa214591de7435ba3192cb96742e232 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T18:05:27Z |
| publishDate | 2022-03-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-9fa214591de7435ba3192cb96742e2322022-12-22T03:22:00ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-03-0115310.1242/dmm.049234049234Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesisAjai J. Pulianmackal0Kiriaki Kanakousaki1Kerry Flegel2Olga G. Grushko3Ella Gourley4Emily Rozich5Laura A. Buttitta6 Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA 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.http://dmm.biologists.org/content/15/3/dmm049234drosophila wingnuclear pore complexribosome biogenesisjnk signalingapoptosiscompensatory proliferation |
| spellingShingle | Ajai J. Pulianmackal Kiriaki Kanakousaki Kerry Flegel Olga G. Grushko Ella Gourley Emily Rozich Laura A. Buttitta Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis Disease Models & Mechanisms drosophila wing nuclear pore complex ribosome biogenesis jnk signaling apoptosis compensatory proliferation |
| title | Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis |
| title_full | Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis |
| title_fullStr | Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis |
| title_full_unstemmed | Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis |
| title_short | Misregulation of Nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis |
| title_sort | misregulation of nucleoporins 98 and 96 leads to defects in protein synthesis that promote hallmarks of tumorigenesis |
| topic | drosophila wing nuclear pore complex ribosome biogenesis jnk signaling apoptosis compensatory proliferation |
| url | http://dmm.biologists.org/content/15/3/dmm049234 |
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