China
Africa
Explore chapters and articles related to this topic
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Signal transduction also depends on the controlled movement of signal transduction proteins within the cell. One of the most important transport events is the bidirectional shuttling (i.e. translocation) of signal transduction proteins between the cytosol and the nucleus. In some cases, such movement depends on the activation of a nuclear localisation signal or sequence (NLS) on a protein. NLSs are recognised by proteins that transport protein cargo through nuclear pores from the cytosol into the nucleus of a cell. Usually, the activation of NLS involves protein modification or a change in protein-protein interaction, which exposes the NLS. For example, NF-κB is bound to its inhibitor, IκB, when it is in the cytosol. This is because IκB masks the NLS of NF-κB, which prevents it from transiting into the nucleus. In a similar manner, binding of class IIa histone deacetylases (HDACs) with the chaperone protein 14-3-3 masks the NLS and exposes the nuclear export sequence (NES) resulting in nuclear export and cytosolic retention of HDAC4. Phosphorylation of three serine residues (Ser246, Ser467 and Ser632) plays a key role in modulating HDAC4 translocation by increasing 14-3-3 binding and leading to nuclear export and the de-repression of gene transcription.
TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
The TP53 protein (Figure 1) consists of several functional domains (Ko and Prives, 1996). The N-terminal sequence (amino acids 1–50) contains a transactivation domain, involved in the modulation of transcription of target genes. This locus is also responsible for the interaction with MDM2, a protein with ubiquitin ligase activity that controls proteasomal degradation of TP53 (see below) (Kussie et al., 1996; Lin et al., 1998). The central core domain between amino acids 100 and 300 participates directly in recognition and binding with specific DNA sequences (Cho et al., 1994). A locus between amino acids 323 and 356 is responsible for oligomerization of TP53 molecules into tetramers (Kussie et al., 1996; Lin et al., 1994), the form in which this protein functions in the cell (McLure and Lee, 1998). A nuclear export signal lies within the tetramerization domain (Stommel et al., 1999), which is positioned between the first and second of three nuclear localization signals spanning through amino acids 316–325, 369–375 and 379–384 (Shaulsky et al., 1990). The C-terminal domain (amino acids 363–393) is essential for the regulation of TP53 activity and is a target for modification by kinases, acetylases, glycosylases, and for binding with other interacting proteins. In addition, the C-terminal TP53 fragment is able to bind nonspecifically to single-stranded DNA regions, unpaired bases, and DNA ends (Bakalkin et al., 1995), indicating its possible involvement in the process of recognition of damaged DNA.
TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2022
Yara Al Ojaimi, Audrey Dangoumau, Hugo Alarcan, Rudolf Hergesheimer, Patrick Vourc’h, Philippe Corcia, Débora Lanznaster, Hélène Blasco
Contrary to these studies, it was shown that the nuclear egress of TDP-43 is size-dependent and happens through passive diffusion rather than active transport [65]. The nuclear export signal (NES) of TDP-43 was found to not be accessible to export receptors and is therefore considered nonfunctional [65]. Complementary to these findings, Archbold et al suggested that overlapping pathways regulate the nuclear export of TDP-43 and therefore preventing the accumulation of cytoplasmic TDP-43 would require targeting several of these mechanisms at the same time [64]. Studies that linked the decreased cellular toxicity of TDP-43 to a mutated NES or to inhibited export receptors did not consider the indirect effects of such changes on mechanisms such as TDP-43 solubility, RNA processing, SG formation, or the export of other nuclear proteins. Consequently, enhancing the nuclear retention of TDP-43 seems to be a more reliable strategy to reduce TDP-43 mislocalization than inhibiting the nuclear export of TDP-43.
Is it accurate to classify ALS as a neuromuscular disorder?
Published in Expert Review of Neurotherapeutics, 2020
Michael A. van Es, H. Stephan Goedee, Henk-Jan Westeneng, Tanja C.W. Nijboer, Leonard H. van den Berg
The TDP-43 protein consists of 414 amino acid residues and can bind both DNA and RNA and has multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Under physiological conditions TDP-43 generally resides in the nucleus. It has a nuclear export signal as well as nuclear localization signal, which means it can shuttle back and forth between nucleus and cytoplasm. The exact role of TDP-43 in the pathophysiology of ALS remains to be elucidated, but there is emerging evidence that dysregulation of TDP-43 expression plays an important role. When in nuclear excess TDP-43 binds the 3′UTR within its own pre-mRNA, which leads the use of alternative polyadenylation signals and splicing events causing these mRNA transcripts to be degraded. This feedback loop therefore auto-regulates the expression of TDP-43. Both loss of function and overexpression have been implicated in the pathogenesis.
Interaction of the mTERT telomerase catalytic subunit with the c-Abl tyrosine kinase in mouse granulosa cells
Published in Journal of Receptors and Signal Transduction, 2020
Aylin Yaba, Sami Agus, Ecem Yıldırım, Cihan Süleyman Erdogan, Bayram Yılmaz
Abelson Tyrosine Kinase (c-Abl) is a non-receptor protein tyrosine kinase [10] that encodes a nuclear and cytoplasmic protein tyrosine kinase which has known be involved in processes of cell proliferation, differentiation, adhesion, and stress response [11,12]. The c-Abl tyrosine kinase has a nuclear-import and a nuclear-export signal, in addition to presenting a nucleo-cytoplasmic shuttling during cell proliferation [13]. c-Abl protein tyrosine kinase is activated when double-strand DNA breaks are comprised [8]. The nuclear isoform of c-Abl orchestrates cell cycle during G1-S transition and relations with several proteins involved in DNA repair as a response to oxidative stress or ionizing radiation [12] besides regulating cytoskeletal structure, cell division, cell growth, and cell proliferation [14,15].