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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
HDAC3’s phospho-acceptor site, S424, which is a non-conserved residue among the Class I HDACs, when mutated to alanine severely compromises enzymatic activity of HDAC1 and HDAC2. Unlike HDAC1 and HDAC2, the HDAC3 associates with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1), and dephosphorylation of HDAC3 by PP4 down-regulates HDAC3 enzymatic activity (Zhang et al., 2005). Phosphorylation of HDAC8 at S39 leads to the disruption in the surface structure, which ultimately leads to the negative effect of HDAC8. Phosphorylation of Class IIa HDACs may lead to their ubiquitination and proteasomal degradation. Two phosphatases have been implicated in the regulation of Class IIa HDACs activities and functions: protein phosphatase 1b (PP1b), including myosin phosphatase targeting subunit 1 (MYPT1, a regulatory subunit of PP1), and protein phosphatase 2A (PP2A). Class IIb HDACs, global proteomic profiling of phosphopeptides, revealed that HDAC6 is phosphorylated at S22 and T30 (Beausoleil et al., 2004).
Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
Phosphatases, through their ability to counterbalance kinase activity, can be used to inhibit NF-κB activation. Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, blocks the activity of IKKβ. Anti-leukemic drug, cytarabine, inhibits NF-κB by dephosphorylating p65 through PP2A and B [168]. PP2C family member, PPM1A, has been reported to dephosphorylate RelA, and inhibit NF-κB activity and cancer invasiveness [169]. Another member of PP2C family, WIP1, dephosphorylates p65 subunit of NF-κB, thus inhibiting NF-κB activation, and, consequently, the mice lacking WIP1 exhibit enhanced inflammation [170].
Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Tasnuva Sarowar, Md. Hafiz Uddin
The tau protein in neurofibrillary tangles become hyperphosphorylated which changes the conformation of tau helices, leading to disruption in tau-microtubule association. Eventually, this leads to loss of necessary cellular function and cell death (Iqbal et al. 1998). Hyperphosphorylated tau is not only found in AD brains but also in a number of other neurodegenerative diseases, such as corticobasal degeneration, frontotemporal dementia, and Niemann pick disease (Wang, Wang, and Tian 2014). The phosphorylation of tau protein can be mediated by several kinases and phosphatases, such as glycogen synthase kinase 3 beta (GSK3β), cyclin-dependent kinase (CDK5), and extracellular signal-related kinases. The phosphorylation via GSK3β can be reversed by protein phosphatase 2A (PP2A). Thus, activation of GSK3β and inhibition of PP2A can lead to a vicious cycle. Due to hyperphosphorylation, tau can form paired helical form aggregates that disrupt the microtubule dynamics (Avila et al. 2004).
Identification of key pathways and genes in the progression of silicosis based on WGCNA
Published in Inhalation Toxicology, 2022
Jiaqi Lv, Jingwei Xiao, Qiang Jia, Xiangjing Meng, Zhifeng Yang, Shuangshuang Pu, Ming Li, Tao Yu, Yi Zhang, Haihua Wang, Li Liu, Zhongsheng Li, Xiao Chen, Haitao Yang, Yulu Li, Mengyun Qiao, Airu Duan, Hua Shao, Bin Li
mRNA levels of genes were determined by real-time fluorescence quantitative PCR (RT-qPCR). Trizol reagent (15596018, Invitrogen, Carlsbad, CA, USA) was used to extract total RNA from lung tissues. mRNA was reversely transcribed into cDNA using a mRNA cDNA Synthesis Kit (GPQ1803, GenePool Biotech, Beijing, China). mRNA/lncRNA qPCR Kit (GPQ1808, GenePool Biotech, Beijing, China) was used to amplify cDNA in a Line Gene 9600 Plus system (Bioer Technology, Hangzhou, China). The expression of mRNA was normalized to GAPDH expression, and the primers used in this experiment were listed in Supplementary Table 2. The protein level of PP2Ac (the catalytic subunit of protein phosphatase 2 A) was detected by Western blotting. The Western blotting protocol for PP2Ac was consistent with the one in the establishment and validation of the rat model for silicosis fibrosis. The dilution rate of the PP2Ac antibody (2038, CST, Massachusetts, America) was 1:2000.
The Expression and Role of microRNA-133a in Plasma of Patients with Kawasaki Disease
Published in Immunological Investigations, 2022
Yeping Luo, Meng Yu, Pengzhu Li, Lihua Huang, Jiping Wu, Min Kong, Ying Li, Zhixiang Wu, Zhijuan Kang, Lu Yi, Zuocheng Yang
PPP2CA is the catalytic submit of protein phosphatase 2A (PP2A). PP2A is the main serine/threonine phosphatase in organism which control dephosphorylation of thousands of phosphoprotein substrates(Kolupaeva 2019; Shi 2009). The dephosphorylation of PP2A is associated with regulating the interity and permeability of vascular endothelial by influencing adhesion connection, tight connection, and the coordination of cytoskeletal components (Le Guelte et al. 2012; Tar et al. 2006). PPP2A also involves in wnt signaling pathway and maintains the stability of VE-cadherin-catenin complex that can prevent the increase of vascular endothelial permeability (Giannotta et al. 2013; Rho et al. 2017; Schulte et al. 2011). Phosphorylation of catenin at Tyr will prevent their interaction and lead to the cleavage of the complex’s extracellular domain which can be detected after dissociation in blood called sVE-cadherin (Kasa et al. 2013; Vilgrain et al. 2013).
Overexpression of cancerous inhibitor ofPP2A (CIP2A) in acute myeloid leukemia
Published in Expert Review of Hematology, 2022
Reem Hasanin, Ghada Mossallam, Sally Elfishawi, Ahmed Rabea, Nayera Hamdy
Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase and tumor suppressor that negatively regulates numerous signal transduction pathways involved in cell proliferation, differentiation, and survival [5]. PP2A inhibition is a common event in AML [6]. Restoration of PP2A activity induces cell growth arrest and caspase-dependent apoptosis suggesting that PP2A inactivation plays a crucial role in AML and its activation represents a potential novel therapeutic target [6,7]. Cancerous inhibitor of PP2A (CIP2A) is identified as an endogenous inhibitor of PP2A. It inhibits PP2A-mediated dephosphorylation of the oncogene kinase c-MYC in human malignancies [7]. CIP2A is overexpressed in several human malignancies, including hematologic malignancies, especially in newly diagnosed AML patients and at relapse [8,9]. CIP2A overexpression was shown to be a recurrent event in cytogenetic normal AML patients with a poor prognostic impact on the overall survival and was also associated with disease progression to blast crisis in chronic myeloid leukemia (CML) [9,10].