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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Class IIa HDACs (HDAC 4, 5, 7 and 9) harbor a unique adapter domain in the N-terminus to facilitate the attachment of DNA-binding transcription factor MEF2 (Kee and Kook, 2011). Furthermore, the phosphorylation sites present in the C-terminus of Class Ia HDACs act as regulatory signals for the association of 14–3–3 proteins (Martin et al., 2007; Seto and Yoshida, 2014). In addition to the binding of 14–3–3- proteins, Class IIa HDACs form multimeric protein complexes with silencing mediator of retinoid and thyroid hormone receptors (SMRT)/nuclear hormone receptor co-repressor (N-CoR)-HDAC3 complex, thereby regulate chromatin modifications (Park et al., 2018). This class plays a key role in deacetylation reactions involving low enzymatic activity (Fischle et al., 2002).
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The processes of DA synthesis by TH and DDC and its transport into storage vesicles by VMATs have long been viewed as two separate and independent events. However, several lines of evidence, employing co-immunoprecipitation, overexpression, mutagenesis, and in vitro binding assays, revealed that VMAT2 and the DA biosynthetic enzymes are physically and functionally coupled at the synaptic vesicle membrane [69]. The coupling complex also includes scaffolding proteins such as 14-3-3 protein and synuclein. Although TH is commonly considered a cytosolic enzyme, it exists in both cytosolic and membrane-bound forms. Cytosolic TH is enriched in neuronal somato–dendritic compartments of the substantia nigra and ventral tegmental area, whereas membrane-bound TH is more common in brain areas enriched in axon terminals (e.g., striatum and nucleus accumbens).
Intracellular Peptide Turnover: Properties and Physiological Significance of the Major Peptide Hydrolases of Brain Cytosol
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
Hui et al. provided evidence for two isozymes of c-AAP in chicken brain132. Two forms of the soluble enzyme designated SI and SII were separated by Bio Gel HTP® chromatography. SI is a monomer of 105,000 whereas SII is composed of two polypeptides of 100,000 and 25,000. The catalytic properties of both forms are similar, however tryptic peptide maps differ. Amino acid sequence of fragments was reported as not identical but homologous. Interestingly, sequence homology to a brain specific 14-3-3 protein was found. This protein is a protein kinase activator of tyrosine and tryptophan hydroxylases. The possible regulation of c-AAP has not been extensively explored. The purified monkey brain enzyme was stimulated four-fold by 1mM ATP + 4 mM Mg++133. This effect was due to a change in the Vmax of the enzyme. However phosphorylation was not the underlying mechanism since these investigators found a similar effect with non-hydrolyzable analogs of ATP and could find no evidence for phosphorylation. It was proposed that ATP activates by reversibly binding to a site on the enzyme. The enzyme can also be phosphorylated by the catalytic subunit of cAMP-dependent protein kinase. In this case, phosphorylation leads to a decrease in enzymatic activity. It is not known how these changes relate to the regulation of c-AAP in vivo.
14-3-3 proteins at the crossroads of neurodevelopment and schizophrenia
Published in The World Journal of Biological Psychiatry, 2022
André S. L. M. Antunes, Verônica M. Saia-Cereda, Fernanda Crunfli, Daniel Martins-de-Souza
14-3-3 proteins regulate their targets through inhibition, activation, structural stabilisation, translocation and regulation of target degradation (reviewed in Rosenquist 2003; Fan et al. 2019). The structural effects of 14-3-3 proteins binding to their targets are: conformational changes and physical occlusion of sequence-specific or structural protein features (reviewed in Alastair Aitken 2006). Regarding their physiological functions, 14-3-3 proteins may exert effects on the subcellular localisation, activity and stability of their targets. They may regulate ubiquitination and degradation or block the action of phosphatases on their target by occlusion (Tzivion and Avruch 2002). For instance, occlusion by 14-3-3 proteins has been shown to block protein-DNA interactions and to prevent nuclear localisation signal (NLS)-mediated translocation (Brunet et al. 2002; Obsil et al. 2003). In addition, 14-3-3 proteins can serve as rigid scaffolding structures that are able to induce direct conformational alterations in their targets (Obsil et al. 2001) and to bind targets, promoting the formation of protein complexes (Ottmann et al. 2007) (Figure 1).
Atypical and early symptoms of sporadic Creutzfeldt – Jakob disease: case series and review of the literature
Published in International Journal of Neuroscience, 2021
Grammatiki Katsikaki, Ioannis E. Dagklis, Petros Angelopoulos, Dimitrios Ntantos, Angeliki Prevezianou, Sevasti Bostantjopoulou
The first case was a 60-year-old woman who had blurred vision with gradual deterioration, without pathological findings from ophthalmological evaluation. Two months later, a gait disorder was added to her clinical picture. Magnetic Resonance Imaging (MRI) exhibited diffusion restriction in caudate nucleus bilaterally as well as in the right parietal, temporal and occipital cortex (Figure 1A,B). The disease rapidly evolved into cognitive decline with cortical blindness, pyramidal signs, upper limb mirror movements, dystonia and seizures. The patient died after three months. In sequential brain MRIs during the course of the disease, extension of the increased signal was observed in adjacent areas of the cortex. Electroencephalogram (EEG) recording was pathological with polymorphic slow activity and biphasic and triphasic slow spike-wave complexes. Increased 14-3-3 protein was detected in cerebrospinal fluid (CFS).
14-3-3β Is necessary in the regulation of polarization and directional migration of alveolar myofibroblasts by lipopolysaccharide
Published in Experimental Lung Research, 2020
Then we studied further how TGF/EGFR affected the activity of RhoA, directly or indirectly? It is well known that RhoA act as molecular switch by cycling from GTP bound active state to GDP bound inactive state. The cycling between these two states is positively controlled by GEFs, and negatively regulated by GAPs. Many studies have reported that GAPs, such as DLC1 and Plexin, may combine with 14-3-3 protein.19,36 Ubiquitously expressed in all eukaryotic cells 14-3-3 proteins are small dimeric proteins. Despite having no detectable catalytic or functional domains, 14-3-3 proteins do appear to be regulators of key signaling components and function primarily as chaperones, adaptors and scaffolds. 14-3-3 proteins have seven highly conserved isoforms [β, γ, ζ, σ, ε, η and τ] in mammals, the functions of which appear to be largely similar.1 Among them, 14-3-3β is closely related to many physiological activities, such as cytoskeleton remodeling and cell migration.37 Generally, 14-3-3 proteins bind to their target proteins in a phosphorylation-dependent manner. TGF-α can activate PKC through EGFR, and PKC can make GAPs phosphorylation.36,38 Here, our results show that if we knock down 14-3-3β, TGF-α cannot activate RhoA and disturb myofibroblasts directional migration. Therefore, we suggested that 14-3-3β was a necessary link in the regulation of RhoA by TGF-α/EGFR.