On the Effects of Leukemogenic Nucleoporin Fusion Proteins on Nucleocytoplasmic Transport and Gene Expression

Martins, Natércia C. T.; Mendes, Adélia; Fahrenkrog, Birthe

doi:10.1007/978-3-319-77309-4_10

Cited by 4 publications

(7 citation statements)

References 188 publications

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“…Altogether, GO and clustered pathway analyses of NUP98-HOXA9 suggest that transcription dysregulation is a major defect in NUP98-HOXA9 driven leukemia. NUP98 is essential for CRM1-mediated nuclear export and NUP98 chimeras have been shown to affect CRM1-mediated nuclear export, to an extent, however, that is not fully understood [7,54]. To obtain a deeper insight into the impact of NUP98-HOXA9 on CRM1-mediated nuclear export, we…”

Section: Identification Of Novel Proximal Interactors Of Nup98-hoxa9mentioning

confidence: 99%

“…NUP98 is essential for CRM1-mediated nuclear export and NUP98 chimeras have been shown to affect CRM1-mediated nuclear export, to an extent, however, that is not fully understood [7,54]. To obtain a deeper insight into the impact of NUP98-HOXA9 on CRM1-mediated nuclear export, we screened the list of NUP98-HOXA9 proximal interactors for the presence of classical NESs using two algorithms: NES finder 0.2 and LocNES [43,44].…”

Section: Nup98-hoxa9 Proximal Interactors Are Enriched In Nuclear Expmentioning

confidence: 99%

“…A number of chromosomal translocations involving the NUP98 and NUP214 loci are reported in acute myeloid and lymphoblastic leukemias (AML and ALL, respectively). NUP98-and NUP214-related leukemia are associated with poor overall survival [4][5][6][7], and no specific or targeted therapies are as yet available to improve prognosis. The chromosomal rearrangements of NUP98 and NUP214 result in their fusion with a large range of gene partners, all of which retain the FG domain of the respective nucleoporin [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…NUP98-and NUP214-related leukemia are associated with poor overall survival [4][5][6][7], and no specific or targeted therapies are as yet available to improve prognosis. The chromosomal rearrangements of NUP98 and NUP214 result in their fusion with a large range of gene partners, all of which retain the FG domain of the respective nucleoporin [7,8]. The fusion of NUP98 with the homeobox protein Hox-A9 (HOXA9), NUP98-HOXA9, that results from t(7;11)(p15;p15), has been studied as the prototype for the oncogenic mechanisms governing the actions of NUP98 fusions with homeodomain (HD) proteins in AML [9].…”

Section: Introductionmentioning

confidence: 99%

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Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Mendes

Jühlen

Bousbata

et al. 2020

Cells

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The interaction of oncogenes with cellular proteins is a major determinant of cellular transformation. The NUP98-HOXA9 and SET-NUP214 chimeras result from recurrent chromosomal translocations in acute leukemia. Functionally, the two fusion proteins inhibit nuclear export and interact with epigenetic regulators. The full interactome of NUP98-HOXA9 and SET-NUP214 is currently unknown. We used proximity-dependent biotin identification (BioID) to study the landscape of the NUP98-HOXA9 and SET-NUP214 environments. Our results suggest that both fusion proteins interact with major regulators of RNA processing, with translation-associated proteins, and that both chimeras perturb the transcriptional program of the tumor suppressor p53. Other cellular processes appear to be distinctively affected by the particular fusion protein. NUP98-HOXA9 likely perturbs Wnt, MAPK, and estrogen receptor (ER) signaling pathways, as well as the cytoskeleton, the latter likely due to its interaction with the nuclear export receptor CRM1. Conversely, mitochondrial proteins and metabolic regulators are significantly overrepresented in the SET-NUP214 proximal interactome. Our study provides new clues on the mechanistic actions of nucleoporin fusion proteins and might be of particular relevance in the search for new druggable targets for the treatment of nucleoporin-related leukemia.

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Section: Identification Of Novel Proximal Interactors Of Nup98-hoxa9mentioning

confidence: 99%

Section: Nup98-hoxa9 Proximal Interactors Are Enriched In Nuclear Expmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Mendes

Jühlen

Bousbata

et al. 2020

Cells

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“…They may occur as a consequence of previous cancer therapy, but also de novo. To date, 30 different partners for NUP98 are known, which fall into two main categories: homeodomain (HD) or non-HD chromatin binding proteins [39,40,41]. Arrest of cellular differentiation and upregulation of clustered HOX genes are common to all NUP98 fusion proteins [42,43,44,45].…”

Section: Introductionmentioning

confidence: 99%

NUP214 in Leukemia: It’s More than Transport

Mendes

Fahrenkrog

2019

Cells

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NUP214 is a component of the nuclear pore complex (NPC) with a key role in protein and mRNA nuclear export. Chromosomal translocations involving the NUP214 locus are recurrent in acute leukemia and frequently fuse the C-terminal region of NUP214 with SET and DEK, two chromatin remodeling proteins with roles in transcription regulation. SET-NUP214 and DEK-NUP214 fusion proteins disrupt protein nuclear export by inhibition of the nuclear export receptor CRM1, which results in the aberrant accumulation of CRM1 protein cargoes in the nucleus. SET-NUP214 is primarily associated with acute lymphoblastic leukemia (ALL), whereas DEK-NUP214 exclusively results in acute myeloid leukemia (AML), indicating different leukemogenic driver mechanisms. Secondary mutations in leukemic blasts may contribute to the different leukemia outcomes. Additional layers of complexity arise from the respective functions of SET and DEK in transcription regulation and chromatin remodeling, which may drive malignant hematopoietic transformation more towards ALL or AML. Another, less frequent fusion protein involving the C terminus of NUP214 results in the sequestosome-1 (SQSTM1)-NUP214 chimera, which was detected in ALL. SQSTM1 is a ubiquitin-binding protein required for proper autophagy induction, linking the NUP214 fusion protein to yet another cellular mechanism. The scope of this review is to summarize the general features of NUP214-related leukemia and discuss how distinct chromosomal translocation partners can influence the cellular effects of NUP214 fusion proteins in leukemia.

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Multifunctionality of F-rich nucleoporins

Heinß

Sushkin

et al. 2020

Biochemical Society Transactions

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Nucleoporins (Nups) represent a range of proteins most known for composing the macromolecular assembly of the nuclear pore complex (NPC). Among them, the family of intrinsically disordered proteins (IDPs) phenylalanine-glycine (FG) rich Nups, form the permeability barrier and coordinate the high-speed nucleocytoplasmic transport in a selective way. Those FG-Nups have been demonstrated to participate in various biological processes besides nucleocytoplasmic transport. The high number of accessible hydrophobic motifs of FG-Nups potentially gives rise to this multifunctionality, enabling them to form unique microenvironments. In this review, we discuss the multifunctionality of disordered and F-rich Nups and the diversity of their localizations, emphasizing the important roles of those Nups in various regulatory and metabolic processes.

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On the Effects of Leukemogenic Nucleoporin Fusion Proteins on Nucleocytoplasmic Transport and Gene Expression

Cited by 4 publications

References 188 publications

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

NUP214 in Leukemia: It’s More than Transport

Multifunctionality of F-rich nucleoporins

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