scholarly journals Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Stress Responses ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Human Tumor ◽  
Docking Simulation ◽  
Md Simulations ◽  
Tumor Promoter ◽  
Dynamic Conditions ◽  
Lead Compounds ◽  
Phosphatase 2A

Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A-αprotein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A-αprotein.

scholarly journals Subunits B′γand B′ζof protein phosphatase 2A regulate photo-oxidative stress responses and growth inArabidopsis thaliana

2015 ◽  
Vol 38 (12) ◽  
pp. 2641-2651 ◽  
Author(s):  
Grzegorz Konert ◽  
Moona Rahikainen ◽  
Andrea Trotta ◽  
Guido Durian ◽  
Jarkko Salojärvi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Phosphatase 2A ◽  
Oxidative Stress Responses

scholarly journals Phosphoproteome and drug-response effects mediated by the three protein phosphatase 2A inhibitor proteins CIP2A, SET, and PME-1

2020 ◽  
Vol 295 (13) ◽  
pp. 4194-4211 ◽  
Author(s):  
Otto Kauko ◽  
Susumu Y. Imanishi ◽  
Evgeny Kulesskiy ◽  
Laxman Yetukuri ◽  
Teemu Daniel Laajala ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Rna Splicing ◽  
Protein Phosphatase 2A ◽  
Human Tumor ◽  
Nuclear Lamina ◽  
Cellular Regulation ◽  
Cellular Processes ◽  
Phosphatase 2A ◽  
A Subunit ◽  
Cellular Pathways

Protein phosphatase 2A (PP2A) critically regulates cell signaling and is a human tumor suppressor. PP2A complexes are modulated by proteins such as cancerous inhibitor of protein phosphatase 2A (CIP2A), protein phosphatase methylesterase 1 (PME-1), and SET nuclear proto-oncogene (SET) that often are deregulated in cancers. However, how they impact cellular phosphorylation and how redundant they are in cellular regulation is poorly understood. Here, we conducted a systematic phosphoproteomics screen for phosphotargets modulated by siRNA-mediated depletion of CIP2A, PME-1, and SET (to reactivate PP2A) or the scaffolding A-subunit of PP2A (PPP2R1A) (to inhibit PP2A) in HeLa cells. We identified PP2A-modulated targets in diverse cellular pathways, including kinase signaling, cytoskeleton, RNA splicing, DNA repair, and nuclear lamina. The results indicate nonredundancy among CIP2A, PME-1, and SET in phosphotarget regulation. Notably, PP2A inhibition or reactivation affected largely distinct phosphopeptides, introducing a concept of nonoverlapping phosphatase inhibition- and activation-responsive sites (PIRS and PARS, respectively). This phenomenon is explained by the PPP2R1A inhibition impacting primarily dephosphorylated threonines, whereas PP2A reactivation results in dephosphorylation of clustered and acidophilic sites. Using comprehensive drug-sensitivity screening in PP2A-modulated cells to evaluate the functional impact of PP2A across diverse cellular pathways targeted by these drugs, we found that consistent with global phosphoproteome effects, PP2A modulations broadly affect responses to more than 200 drugs inhibiting a broad spectrum of cancer-relevant targets. These findings advance our understanding of the phosphoproteins, pharmacological responses, and cellular processes regulated by PP2A modulation and may enable the development of combination therapies.

scholarly journals The Adenovirus E4orf4 Protein Induces G2/M Arrest and Cell Death by Blocking Protein Phosphatase 2A Activity Regulated by the B55 Subunit

2009 ◽  
Vol 83 (17) ◽  
pp. 8340-8352 ◽  
Author(s):  
Suiyang Li ◽  
Claudine Brignole ◽  
Richard Marcellus ◽  
Sara Thirlwell ◽  
Olivier Binda ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Growth Arrest ◽  
Human Tumor ◽  
Cell Killing ◽  
Pp2a Activity ◽  
Phosphatase 2A

ABSTRACT Human adenovirus E4orf4 protein is toxic in human tumor cells. Its interaction with the Bα subunit of protein phosphatase 2A (PP2A) is critical for cell killing; however, the effect of E4orf4 binding is not known. Bα is one of several mammalian B-type regulatory subunits that form PP2A holoenzymes with A and C subunits. Here we show that E4orf4 protein interacts uniquely with B55 family subunits and that cell killing increases with the level of E4orf4 expression. Evidence suggesting that Bα-specific PP2A activity, measured in vitro against phosphoprotein substrates, is reduced by E4orf4 binding was obtained, and two potential B55-specific PP2A substrates, 4E-BP1 and p70S6K, were seen to be hypophosphorylated in vivo following expression of E4orf4. Furthermore, treatment of cells with low levels of the phosphatase inhibitor okadaic acid or coexpression of the PP2A inhibitor I1 PP2A enhanced E4orf4-induced cell killing and G2/M arrest significantly. These results suggested that E4orf4 toxicity results from the inhibition of B55-specific PP2A holoenzymes, an idea that was strengthened by an observed growth arrest resulting from treatment of H1299 cells with Bα-specific RNA interference. We believe that E4orf4 induces growth arrest resulting in cell death by reducing the global level of B55-specific PP2A activity, thus preventing the dephosphorylation of B55-specific PP2A substrates, including those involved in cell cycle progression.

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