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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
The nuclear pore complex is the gateway for the transport of many types of proteins and RNAs into the nucleus. These include replication enzymes, nucleolar proteins, steriod hormone receptor complexes, transcription factors, histones, messenger RNA, U snRNAs, and ribosomal RNA. Small molecules with molecular weights less than 60,000 to 70,000 Da can diffuse freely into the nucleus, while macromolecules larger than 90 Å in diameter require nuclear localizing sequences (NLS) to facilitate transport through the NPC. Indeed, some small proteins like histone H1 (21 kDa) also display NLS and bind to cytoplasmic receptors and are actively transported into the nucleus (116). Both proteins and RNAs (snRNPs, rRNAs) display bidirectionality with respect to transport. Following an introduction to nuclear localizing sequences, we will describe transport for each class of molecule.
Mechanism of Transfection
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
We shall follow a genosome with given physicochemical characteristics which determine its biological properties during the transfection process. Its stability and interaction characteristics dictate its fate in biological systems, and we shall look at interactions with cells, genosome/DNA entry into the cytoplasm, and interactions in the cytoplasm leading to the entry into the nucleus. Because we can, at present, control mostly behavior up to the DNA release in the cell cytoplasm, we shall concentrate on the first part of the transfection, i.e., transfer of plasmid from the outside of the cell into the cytoplasm. The second part of transfection, consisting of the transfer of the plasmid from cytoplasm into the nucleus, is still very obscure. It is possible that it can be better controlled by special DNA inserts than by delivery vehicles. While there is a constant efflux of nucleic acids from the cell nucleus, there are in nature only viral and spermal DNA which efficiently travel in the opposite direction. There are, however, many proteins which shuttle through the nuclear membrane, including transporters, nucleoporins, and others, which may contain nuclear localization sequences. These are regions rich in basic amino acids and can bind nucleic acids. Such complexes enter nuclei through a nuclear pore complex, a protein which regulates a pore with diameter of approximately 100 nm.
Imaging of Intracellular Targets
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Intracellular targets also include those situated in the cell nucleus and, in order to reach these, another barrier needs to be overcome: the nuclear envelope, a double membrane that is continuous with the endoplasmic reticulum. All transport across this membrane exclusively occurs via the nuclear pore complexes, which are embedded in the nuclear envelope. Although passive diffusion through these complexes is possible for molecules up to 45 kDa (ions, metabolites, and smaller proteins), active transport is the predominant mechanism to transfer molecules to and from the nucleus (Gorlich and Kutay 1999; van der Aa et al. 2006). This nucleocytoplasmic transport is described well by Conti and Izaurralde (2001).
Application of three-dimensional Raman imaging to determination of the relationship between cellular localization of diesel exhaust particles and the toxicity
Published in Toxicology Mechanisms and Methods, 2022
Langying Ou, Akiko Honda, Natsuko Miyasaka, Sakiko Akaji, Issei Omori, Raga Ishikawa, Yinpeng Li, Kayo Ueda, Hirohisa Takano
The 3D image in Figure 2 possibly indicates that DEPs (shown in red) were existed in the cytoplasm (shown in green) as well as in the nucleus (shown in blue). Currently, it is believed that the structure of the nuclear pore complex core has a diameter of approximately 110 nm (Knockenhauer and Schwartz 2016) and an inner diameter of approximately 40 nm (Kabachinski and Schwartz 2015). These values were consistent with those reported by Panté and Kann (2002), who suggested that the nuclear pore is able to transfer macromolecules with diameters up to 39 nm. Oxidized carbon black particles have also been detected in both the cytoplasm and nuclei of RAW 264.7 and CaSki cells (Amornwachirabodee et al. 2018). Moreover, a transmission electron microscopy analysis revealed that C60 particles can enter the nuclei of mature human macrophages (Porter et al. 2006). Therefore, it is possible that, as carbon-based particles, nanosized DEPs can invade the cell nucleus; however, further investigations were needed to conclude whether the particles existed in cell nucleus.
A drug profile on selinexor for the treatment of refractory diffuse large B-cell lymphoma
Published in Expert Review of Hematology, 2022
Macromolecules larger than 40 kDa, such as proteins and RNAs, require active transport to go from the nucleus to the cytoplasm [15]. This transport involves special pores called ‘nuclear pore complex,’ embedded in the nuclear membrane. To pass through these pores, the macromolecules carry specific transport signals that allow them to attach to transport receptors called karyopherins (hence the name ‘Karyopharm’ of the company that produces selinexor), also called ‘exportins,’ for export from nucleus toward the cytoplasm or ‘importins’ for the reentry from the cytoplasm toward the nucleus. There are approximately 20 different karyphorins. The direction of passage is regulated by the GTPase Ran in the nucleus. The RanGTP form binds to exportins and allows the passage toward the cytoplasm where the GTP is dephosphorylated into GDP by GTPase activating protein (GAP). This in turn allows the passage toward the nucleus, after fixation on importins, where RanGTP Exchange Factor (GEF) allows phosphorylation of GDP to GTP (see Figure 2).
TMEM48 promotes cell proliferation and invasion in cervical cancer via activation of the Wnt/β-catenin pathway
Published in Journal of Receptors and Signal Transduction, 2021
Xiao-Ying Jiang, Li Wang, Zong-Yin Liu, Wen-Xia Song, Mi Zhou, Lan Xi
Nuclear pore complexes (NPCs), embedded in nuclear envelopes to promote molecule exchanges between nucleus and cytoplasm, consist of multiple copies of almost 30 different nucleoporins [12]. NPCs not only take part in nucleocytoplasmic transport but also play an essential role in the regulation of genome stability, DNA replication, cell death and other crucial cellular processes [13–15]. Notably, nucleoporin changes have been reported to exert a critical effect on the progression of various cancers [16–18]. With 6 membrane-spanning segments, transmembrane protein 48 (TMEM48) is the most conserved membrane nucleoporin [19]. Mansfeld et al. found an important role of TMEM48 in NPC and nuclear envelope assembly [20]. Moreover, TMEM48 has been demonstrated to be implicated in meiosis and gametogenesis [21]. Recently, TMEM48 has been reported to be closely related to the development of lung cancer [22]. However, little is known about the specific role of TMEM48 in CC.