Inhibition of CRM1-mediated Nuclear Export of Transcription Factors by Leukemogenic NUP98 Fusion Proteins

Takeda, Akihiro; Sarma, Nayan J.; Abdul-Nabi, Anmaar; Yaseen, Nabeel R.

doi:10.1074/jbc.m109.048785

Cited by 53 publications

(43 citation statements)

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“…3A). It has been reported that Nup98 fusion proteins stimulate NFAT (nuclear factor of activated T cells)-and NF-B-mediated transcription activities by impairing the function of XPO1 (52). Thus, we examined the effects of Nup214 fusion proteins on the NF-B signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Saito

Cigdem

Okuwaki

et al. 2016

Molecular and Cellular Biology

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c Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEKNup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-B signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-B-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IB, in the nucleus. These results suggest that SETNup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system. Biological macromolecules are transported between the nucleus and the cytoplasm in response to extracellular signals. Transport of molecules with a molecular mass greater than 40 kDa does not occur by simple diffusion but is generally facilitated by nuclear transport receptors (NTRs) through nuclear pore complexes (NPCs) embedded in the nuclear envelope (1-3). Controlled nuclear-cytoplasmic transport plays important roles in maintaining cellular integrity in eukaryotic cells. It is reported that aberrant subcellular localization of some proteins is associated with various cancer cases (4). p53 has nuclear localization signals (NLSs) and nuclear export signals (NESs), and the accumulation of p53 in the cytoplasm has been reported to be a prognostic indicator in cancer (5). The nuclear factor B (NF-B) transcription factor is observed mainly in the cytoplasm in normal cells, whereas in many cancer cells, it is localized largely in the nucleus (6).In addition to aberrant subcellular localization of proteins in cancer, mutations of genes encoding NTRs and NPC components are found in various types of cancer (7). Mutations of exportin-5 (XPO5) and exportin-1 (XPO1)/CRM1, members of export receptors (8-10), are found in solid cancer and leukemia, respectively. Four nucleoporins-Nup98, Nup214/CAN, Nup358/ RanBP2, and Tpr-have been reported to form chimeric proteins by chromosomal translocations mainly in leukemia (11-15). Nup214, located at the cytoplasmic filament of the NPC, interacts with NTRs to control macromolecular transport....

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Section: Resultsmentioning

confidence: 99%

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Saito

Cigdem

Okuwaki

et al. 2016

Molecular and Cellular Biology

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“…Indeed, both NUP98-HoxA9 and NUP98-DDX10 impair the nuclear export of critical transcriptional regulators, leading to their aberrant nuclear retention and enhanced transcription from responsive promoters. 35 The functional significance of deregulated expression of Hox genes has been suspected in the oncogenic processes of some [17][18][19][20][21] but not all 8,9 NUP98 fusion proteins. Although the expression of HoxA genes was sustained in NUP98-CCDC28A-expressing leukemic cells, this may be related to the enrichment for immature myeloid cells in these populations compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of the NUP98-CCDC28A fusion protein

Petit¹,

Ragu²,

Soler³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe nucleoporin gene NUP98 is rearranged in more than 27 chromosomal abnormalities observed in childhood and adult, de novo and therapy-related acute leukemias of myeloid and T-lymphoid origins, resulting in the creation of fusion genes and the expression of chimeric proteins. We report here the functional analysis of the NUP98-coiled-coil domain-containing protein 28A (NUP98-CCDC28A) fusion protein, expressed as the consequence of a recurrent t(6;11)(q24.1;p15.5) translocation. Design and MethodsTo gain insight into the function of the native CCDC28A gene, we collected information on any differential expression of CCDC28A among normal hematologic cell types and within subgroups of acute leukemia. To assess the in vivo effects of the NUP98-CCDC28A fusion, NUP98-CCDC28A or full length CCDC28A were retrovirally transduced into primary murine bone marrow cells and transduced cells were next transplanted into sub-lethally irradiated recipient mice. ResultsOur in silico analyses supported a contribution of CCDC28A to discrete stages of murine hematopoietic development. They also suggested selective enrichment of CCDC28A in the French-American-British M6 class of human acute leukemia. Primary murine hematopoietic progenitor cells transduced with NUP98-CCDC28A generated a fully penetrant and transplantable myeloproliferative neoplasm-like myeloid leukemia and induced selective expansion of granulocyte/macrophage progenitors in the bone marrow of transplanted recipients, showing that NUP98-CCDC28A promotes the proliferative capacity and self-renewal potential of myeloid progenitors. In addition, the transformation mediated by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, a feature shared by a diverse set of NUP98 fusions. ConclusionsOur results demonstrate that the recurrent NUP98-CCDC28A is an oncogene that induces a rapid and transplantable myeloid neoplasm in recipient mice. They also provide additional evidence for an alternative leukemogenic mechanism for NUP98 oncogenes.

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“…S6). We have previously shown that NUP98-HOXA9 up-regulates NFB-mediated transcription (28). NFB plays a role in erythroid differentiation: it is overexpressed in early erythroid progenitors but is down-regulated during erythroid maturation (59,69).…”

Section: Discussionmentioning

confidence: 99%

“…pGEX6P1-AES, pcDNA3-FLAG-AES, and MSCV-IRES-YFP-FLAG-AES were constructed by subcloning PCR-amplified AES cDNA from pMyr-AES. The construction of NUP98-HOXA9 deletion mutants (28), pGL4.11-KBTBD10 (22), and MSCV-IRES-GFP-HA-NUP98-HOXA9 (25) are described elsewhere. The construction of full-length and deletion mutants of NUP62 and NUP153 are described elsewhere (31).…”

Section: Methodsmentioning

confidence: 99%

Amino-terminal Enhancer of Split (AES) Interacts with the Oncoprotein NUP98-HOXA9 and Enhances Its Transforming Ability

Sarma

Yaseen

2011

Journal of Biological Chemistry

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Background:The oncoprotein NUP98-HOXA9 deregulates transcription and induces cell proliferation leading to acute myeloid leukemia (AML). Results:The transcription factor amino-terminal enhancer of split (AES) interacts with NUP98-HOXA9 and augments its ability to deregulate transcription and proliferation. Conclusion: The data indicate a role for AES in the induction of AML by NUP98-HOXA9. Significance: Understanding the interactions between oncoproteins and transcription factors is important for elucidating the mechanisms of leukemogenesis.

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Inhibition of CRM1-mediated Nuclear Export of Transcription Factors by Leukemogenic NUP98 Fusion Proteins

Cited by 53 publications

References 51 publications

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Functional analysis of the NUP98-CCDC28A fusion protein

Amino-terminal Enhancer of Split (AES) Interacts with the Oncoprotein NUP98-HOXA9 and Enhances Its Transforming Ability

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