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Host-Directed and Immune-Based Therapies for Human Immunodeficiency Virus Infection
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Hernan Valdez, Michael M. Lederman, Bharat Ramratnam, Timothy P. Flanigan
As an obligate intracellular pathogen, HIV, like all viruses, utilizes host elements for each phase of it propagation cycle. Binding, entry, reverse transcription, nuclear transport, integration, transcriptional activation, transcription, cytoplasmic ribonucleic acid (RNA) export, translation, posttranslational protein processing, viral assembly, and budding all require collaboration with host elements. When viewed from the perspective of viral escape, targeting host elements that participate in the viral propagation cycle provides several attractive advantages [5]. Elements encoded on host genes are unlikely to undergo escape mutation. Replication mediated by host polymerases is more faithful, and germ-line mutation is limited by a substantially longer generation time. Moreover, even if somatic mutation resulted in escape of a cell from a host-directed antiviral strategy, selection would not favor survival of this cell and its progeny if it were susceptible to lytic viral infection.
Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
Microinjection, cell permeabilization, and isolated nuclei have been used to study the properties of nucleocytoplasmic transport. Microinjection allows the introduction of material into either the cytoplasmic or nuclear compartments in a living cell. This has been a powerful technique to study diffusion of macromolecules through the cytoplasm, the role of compartmentalization on expression of plasmid DNA, and the factors that regulate macromolecular transport into the nucleus. Digitonin has been effectively employed to permabilize the cell plasma membrane and introduce the substrate and supplemental cytosolic factors to replace proteins which escape while the membranes are compromised (developed by Adam and Gerace; see Ref. 115). This is a common method used to study the requirements for import of proteins into the nucleus. Isolated or reconstituted nuclei have also been used for studying nuclear transport in vitro and permit stringent control of the transport environment. More recently, genetic manipulation via deletion and complementation have been employed to determine the necessity of specific nuclear pore proteins for viability, growth, and transport.
Schinzel−Giedion Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Three putative bipartite NLS motifs are thought to assist the signal-dependent nuclear transport of SETBP1 across the nuclear pore. The AT-hook motifs increase the DNA-binding capacity of SETBP1 and thus enhance its potential in transcriptional regulation.
POM121 overexpression is related to a poor prognosis in colorectal cancer
Published in Expert Review of Molecular Diagnostics, 2020
Tengqi Wang, Haibin Sun, Yinshengboer Bao, Riletu En, Yongjing Tian, Wei Zhao, Lizhou Jia
Nuclear pore membrane protein 121 (POM121) is an important part of the nuclear pore complex (NPC) with wide distribution in vertebrates [7].POM121 has been identified to participate in nuclear envelope assembly and nuclear transport and acts as an NPC anchor [8–10]. Previous studies have focused on the role of POM121 in NPC formation, but increasing evidence has confirmed the versatility of POM121 in other domains. Saito et al. found that N-terminally truncated POM121inhibits HIV-1 replication [11], and Guo et al. demonstrated the role of full-length POM121inefficientHIV-1 nuclear import [12], indicating that POM121 is involved in HIV infection. A recent study showed that POM121 exerts a potent inhibitory effect on macrophage inflammation via the NF-κB signaling pathway [13].POM121 is also reported to be involved in acute lymphoblastic leukemia development by fusing with PAX5 [14,15]and promoting the proliferation and therapeutic resistance of prostate cancer by increasing E2F1, MYC, and AR nuclear import [16].More research is essential to explore the function and mechanism of POM121 in tumorigenesis and progression.
Selinexor (KTP-330) - a selective inhibitor of nuclear export (SINE): anti-tumor activity in diffuse large B-cell lymphoma (DLBCL)
Published in Expert Opinion on Investigational Drugs, 2020
Sharon Ben-Barouch, John Kuruvilla
In the eukaryotic cell, critical cellular processes are carried out within distinct intracellular compartments [7]. Large molecules such as RNA and proteins require active transport between the nucleus and the cytoplasm that occurs at the nuclear transport complex (NPC). Each macromolecule has a nuclear-cytoplasmatic transport signal for nuclear export (NES) or localization (NLS). Three classes of nuclear-cytoplasmatic transport signal have been identified, one of which is a hydrophobic leucine-rich NES recognized by the ubiquitous transport receptor chromosome region maintenance protein 1 (CRM1, also known as XPO1) [8]. Many tumor suppressor proteins (TSPs) and growth-regulatory proteins perform their antineoplastic functions within the nucleus and mechanisms that enhance nuclear export of TSPs could affect their function.
How can an understanding of the C9orf72 gene translate into amyotrophic lateral sclerosis therapies?
Published in Expert Review of Neurotherapeutics, 2019
Sarah H. Berth, Thomas E. Lloyd
The recent discovery that a major cellular process affected by mutated C9orf72 is nucleocytoplasmic transport (NCT) [4–6] has opened promising avenues of research. Using a genetic screen in a Drosophila model expressing GGGGCC repeats, RanGAP, a major regulator of NCT, was identified as a suppressor of NRE toxicity [4]. RanGAP is a GTPase-activating protein (GAP) localized to the cytoplasmic face of the nuclear pore complex (NPC) that stimulates the hydrolysis of RanGTPase in the cytoplasm, favoring importin-mediated nuclear import of proteins containing a nuclear localization sequence (NLS). Importantly, RanGAP is inhibited by the GGGGCC repeat, leading to mislocalization of Ran to the cytoplasm in fly models and also in induced pluripotent stem cells differentiated into neurons (iPSN) from patients with C9orf72 mutation causing ALS [4]. This alteration of the Ran gradient has been shown to disrupt the nuclear import of NLS-containing proteins in fly and iPSN models of C9-ALS. Additionally, accumulation of nuclear transport proteins within stress granules (SGs) in response to cellular stress may be a common pathogenic mechanism in multiple neurodegenerative diseases including C9-ALS [7,8], and thus SGs are a promising therapeutic target upstream of NCT disruption.