scholarly journals Replication of Minute Virus of Mice DNA Is Critically Dependent on Accumulated Levels of NS2

2005 ◽  
Vol 79 (19) ◽  
pp. 12375-12381 ◽  
Author(s):  
Eun-Young Choi ◽  
Ann E. Newman ◽  
Lisa Burger ◽  
David Pintel
Keyword(s):  
Splice Site ◽  
Nuclear Export ◽  
Single Nucleotide ◽  
Minute Virus Of Mice ◽  
U2 Snrna ◽  
Large Intron ◽  
Murine Fibroblasts ◽  
Minute Virus ◽  
Nuclear Export Protein ◽  
Export Protein

ABSTRACT Following transfection of murine fibroblasts, the lymphotropic strain of minute virus of mice (MVMi) does not efficiently produce progeny single-strand DNA (ssDNA). However, changing a single nucleotide in the MVMi 3′ splice site to that found in the fibrotropic strain MVMp enabled full DNA replication and production of ssDNA. This change enhanced excision of the large intron and the production of NS2, likely by improving interaction, in fibroblasts with the branch point-binding U2 snRNA. One function of NS2 involves interaction with the nuclear export protein Crm1. The defect in production of MVMi ssDNA in fibroblasts can also be overcome by introducing a mutation in MVMi NS2 that enhances its interaction with Crm1. Although MVMi contains a 3′ splice site that performs poorly in fibroblasts, MVMi generated at least as much R2 and NS2 in murine lymphocytes as did MVMp in fibroblasts. Therefore, it appears that MVMp has acquired a mutation that improves the excision of the large intron, as it adapted to fibroblasts to accommodate the need for NS2 for replication in these cells, and that the ratio of NS1 to NS2 may play a larger role in the host range of MVM than previously appreciated.

scholarly journals CA- and Purine-Rich Elements Form a Novel Bipartite Exon Enhancer Which Governs Inclusion of the Minute Virus of Mice NS2-Specific Exon in Both Singly and Doubly Spliced mRNAs

1999 ◽  
Vol 19 (1) ◽  
pp. 364-375 ◽  
Author(s):  
Anand Gersappe ◽  
David J. Pintel
Keyword(s):  
Splice Site ◽  
Polypyrimidine Tract ◽  
Minute Virus Of Mice ◽  
Enhancer Element ◽  
Exon Inclusion ◽  
Reading Frame ◽  
Large Intron ◽  
Internal Exon ◽  
Minute Virus

ABSTRACT The alternatively spliced 290-nucleotide NS2-specific exon of the parvovirus minute virus of mice (MVM), which is flanked by a large intron upstream and a small intron downstream, constitutively appears both in the R1 mRNA as part of a large 5′-terminal exon (where it is translated in open reading frame 3 [ORF3]), and in the R2 mRNA as an internal exon (where it is translated in ORF2). We have identified a novel bipartite exon enhancer element, composed of CA-rich and purine-rich elements within the 5′ and 3′ regions of the exon, respectively, that is required to include NS2-specific exon sequences in mature spliced mRNA in vivo. These two compositionally different enhancer elements are somewhat redundant in function: either element alone can at least partially support exon inclusion. They are also interchangeable: either element can function at either position. Either a strong 3′ splice site upstream (i.e., the exon 5′ terminus) or a strong 5′ splice site downstream (i.e., the exon 3′ terminus) is sufficient to prevent skipping of the NS2-specific exon, and a functional upstream 3′ splice site is required for inclusion of the NS2-specific exon as an internal exon into the mature, doubly spliced R2 mRNA. The bipartite enhancer functionally strengthens these termini: the requirement for both the CA-rich and purine-rich elements can be overcome by improvements to the polypyrimidine tract of the upstream intron 3′ splice site, and the purine-rich element also supports exon inclusion mediated through the downstream 5′ splice sites. In summary, a suboptimal large-intron polypyrimidine tract, sequences within the downstream small intron, and a novel bipartite exonic enhancer operate together to yield the balanced levels of R1 and R2 observed in vivo. We suggest that the unusual bipartite exonic enhancer functions to mediate proper levels of inclusion of the NS2-specific exon in both singly spliced R1 and doubly spliced R2.

scholarly journals Characteristics of Nucleocytoplasmic Transport of H1N1 Influenza A Virus Nuclear Export Protein

2014 ◽  
Vol 88 (13) ◽  
pp. 7455-7463 ◽  
Author(s):  
S. Gao ◽  
S. Wang ◽  
S. Cao ◽  
L. Sun ◽  
J. Li ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Nuclear Export ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Export Protein ◽  
Export Protein

scholarly journals Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma

Blood ◽  
2018 ◽  
Vol 132 (24) ◽  
pp. 2546-2554 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Heather Sutherland ◽  
Darrell White ◽  
Michael Sebag ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Low Dose ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Nuclear Retention ◽  
Refractory Multiple Myeloma ◽  
Nuclear Export Protein ◽  
Grade 3 ◽  
Export Protein

Abstract Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

scholarly journals Targeting the Nuclear Export Protein XPO1/CRM1 Reverses Epithelial to Mesenchymal Transition

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Asfar S. Azmi ◽  
Irfana Muqbil ◽  
Jack Wu ◽  
Amro Aboukameel ◽  
William Senapedis ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Nuclear Export Protein ◽  
Export Protein

CRM1 Mediates Nuclear Export of Nonstructural Protein 2 from Parvovirus Minute Virus of Mice

1999 ◽  
Vol 264 (1) ◽  
pp. 144-150 ◽  
Author(s):  
Takayuki Ohshima ◽  
Toshihiro Nakajima ◽  
Takayuki Oishi ◽  
Naoko Imamoto ◽  
Yoshihiro Yoneda ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Nonstructural Protein ◽  
Minute Virus Of Mice ◽  
Nonstructural Protein 2 ◽  
Minute Virus

scholarly journals Splicing of the Large Intron Present in the Nonstructural Gene of Minute Virus of Mice Is Governed by TIA-1/TIAR Binding Downstream of the Nonconsensus Donor

2009 ◽  
Vol 83 (12) ◽  
pp. 6306-6311 ◽  
Author(s):  
Eun-Young Choi ◽  
David Pintel
Keyword(s):  
Rna Processing ◽  
Donor Site ◽  
Minute Virus Of Mice ◽  
Intronic Sequence ◽  
Essential Proteins ◽  
Large Intron ◽  
Minute Virus ◽  
Intronic Splicing Enhancer ◽  
Splicing Enhancer

ABSTRACT The essential proteins NS1 and NS2 of minute virus of mice are encoded by mRNAs R1 and R2, respectively. R2 is derived from R1 by excision of a large intron and thus splicing governs the relative ratios of NS1 and NS2. Excision of the large intron utilizes a nonconsensus 5′ donor site. We identified a U-rich and A-rich intronic sequence immediately downstream of the nonconsensus 5′ donor site that functions as an intronic splicing enhancer (ISE) required for efficient large-intron excision. The ISE binds the cellular RNA-processing proteins TIA-1 and TIAR, which enhance usage of the nonconsensus donor.

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