scholarly journals SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

2018 ◽  
Keyword(s):  
Nuclear Export ◽  
Therapeutic Strategy ◽  
Protein Sequestration

scholarly journals Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells

2016 ◽  
Vol 91 (1) ◽  
Author(s):  
Chuan Li ◽  
Hai-Bo Wang ◽  
Wen-Dong Kuang ◽  
Xiao-Xin Ren ◽  
Shu-Ting Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Nuclear Export ◽  
Therapeutic Strategy ◽  
Host Protein ◽  
Viral Reactivation ◽  
Viral Transcription ◽  
Dependent Manner ◽  
Ltr Promoter ◽  
Hiv 1

ABSTRACT HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4+ T cells. Furthermore, Naf1 knockdown in resting CD4+ T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo. Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy. IMPORTANCE HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.

scholarly journals Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas

Blood ◽  
2016 ◽  
Vol 127 (7) ◽  
pp. 858-868 ◽  
Author(s):  
Biljana Culjkovic-Kraljacic ◽  
Tharu M. Fernando ◽  
Rossella Marullo ◽  
Nieves Calvo-Vidal ◽  
Akanksha Verma ◽  
...  
Keyword(s):  
B Cell ◽  
Nuclear Export ◽  
Therapeutic Strategy ◽  
B Cell Lymphomas ◽  
Partner Protein ◽  
Aggressive Lymphomas ◽  
Key Points

Key Points eIF4E, a protein highly elevated in poor-prognostic lymphomas, simultaneously sustains expression of known driver oncogenes BCL6, BCL2, MYC. The tumorigenic form of Hsp90 is a novel partner protein in the process underlying a new therapeutic strategy for these aggressive lymphomas.

Abstract 3839: Nuclear export (karyopherin) inhibitors: A novel therapeutic strategy for treating Philadelphia-positive (Ph+) acute leukemias

2012 ◽  
Author(s):  
Christopher Walker ◽  
Joshua J. Oaks ◽  
Ramasamy Santhanam ◽  
Paolo Neviani ◽  
Jason G. Harb ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Therapeutic Strategy ◽  
Acute Leukemias ◽  
Novel Therapeutic

Anti-OX40ligand treatment as a novel therapeutic strategy in a murine model of colitis

2001 ◽  
Vol 120 (5) ◽  
pp. A685-A685
Author(s):  
B SINGH ◽  
V MALMSTROM ◽  
F POWRIE
Keyword(s):  
Murine Model ◽  
Therapeutic Strategy ◽  
Novel Therapeutic

Hydroxyurea induces a senescent, non-malignant, immunogenic state in neuroblastoma cells – a new therapeutic strategy?

2010 ◽  
Vol 222 (03) ◽  
Author(s):  
S Taschner-Mandl ◽  
A Kowalska ◽  
H Binder ◽  
D Rieder ◽  
Z Trajanoski ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Neuroblastoma Cells

Increased Thromboxane Biosynthesis in Essential Thrombocythemia

1995 ◽  
Vol 74 (05) ◽  
pp. 1225-1230 ◽  
Author(s):  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Raffaele Tartaglione ◽  
Sergio Cortelazzo ◽  
Tiziano Barbui ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Activation ◽  
Essential Thrombocythemia ◽  
Therapeutic Strategy ◽  
Low Dose ◽  
Thrombotic Risk ◽  
Dose Aspirin ◽  
Gender And Age ◽  
Low Dose Aspirin

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

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