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Results: 1 to 10 of 53

Publication Record


BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.
Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CS
(2017) Gut 66: 852-862
MeSH Terms: Animals, Biomarkers, Tumor, Caco-2 Cells, Carcinogenesis, Cell Adhesion Molecules, Colitis, Colitis, Ulcerative, Colon, Colonic Neoplasms, DNA Methylation, Dextran Sulfate, Down-Regulation, Female, Gene Expression Profiling, HEK293 Cells, Humans, Male, Membrane Proteins, Mice, Mice, Knockout, Muscle Proteins, Promoter Regions, Genetic, Protein Phosphatase 2, Proto-Oncogene Proteins c-myc, RNA, Messenger, Wnt Signaling Pathway
Show Abstract · Added April 15, 2017
OBJECTIVE - Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD.
DESIGN - We determined promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured mRNA levels in a tissue microarray consisting of normal colons and CAC samples. and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels.
RESULTS - mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, was underexpressed in experimental inflammatory carcinogenesis, and mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction.
CONCLUSION - Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. promoter methylation status may serve as a CAC biomarker.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
0 Communities
4 Members
0 Resources
26 MeSH Terms
The three Type 2A protein phosphatases, PP2Ac, PP4c and PP6c, are differentially regulated by Alpha4.
LeNoue-Newton ML, Wadzinski BE, Spiller BW
(2016) Biochem Biophys Res Commun 475: 64-9
MeSH Terms: Adaptor Proteins, Signal Transducing, Catalytic Domain, Gene Knockdown Techniques, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Molecular Chaperones, Phosphoprotein Phosphatases, Protein Phosphatase 2
Show Abstract · Added March 15, 2018
Alpha4 is a non-canonical regulatory subunit of Type 2A protein phosphatases that interacts directly with the phosphatase catalytic subunits (PP2Ac, PP4c, and PP6c) and is upregulated in a variety of cancers. Alpha4 modulates phosphatase expression levels and activity, but the molecular mechanism of this regulation is unclear, and the extent to which the various Type 2A catalytic subunits associate with Alpha4 is also unknown. To determine the relative fractions of the Type 2A catalytic subunits associated with Alpha4, we conducted Alpha4 immunodepletion experiments in HEK293T cells and found that a significant fraction of total PP6c is associated with Alpha4, whereas a minimal fraction of total PP2Ac is associated with Alpha4. To facilitate studies of phosphatases in the presence of mutant or null Alpha4 alleles, we developed a facile and rapid method to simultaneously knockdown and rescue Alpha4 in tissue culture cells. This approach has the advantage that levels of endogenous Alpha4 are dramatically reduced by shRNA expression thereby simplifying interpretation of mutant phenotypes. We used this system to show that knockdown of Alpha4 preferentially impacts the expression of PP4c and PP6c compared to expression levels of PP2Ac.
Copyright © 2016. Published by Elsevier Inc.
0 Communities
1 Members
0 Resources
10 MeSH Terms
WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma.
Wen J, Lee J, Malhotra A, Nahta R, Arnold AR, Buss MC, Brown BD, Maier C, Kenney AM, Remke M, Ramaswamy V, Taylor MD, Castellino RC
(2016) Oncogene 35: 5552-5564
MeSH Terms: Animals, Biomarkers, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cerebellar Neoplasms, Gene Knockdown Techniques, Hedgehog Proteins, Humans, Medulloblastoma, Mice, Mice, Transgenic, NIH 3T3 Cells, Neural Stem Cells, Protein Phosphatase 2C, Signal Transduction, Tumor Suppressor Protein p53
Show Abstract · Added April 25, 2016
High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Visualization of subunit interactions and ternary complexes of protein phosphatase 2A in mammalian cells.
Mo ST, Chiang SJ, Lai TY, Cheng YL, Chung CE, Kuo SC, Reece KM, Chen YC, Chang NS, Wadzinski BE, Chiang CW
(2014) PLoS One 9: e116074
MeSH Terms: Animals, Fluorescent Antibody Technique, Mice, NIH 3T3 Cells, Protein Multimerization, Protein Phosphatase 2, Protein Subunits
Show Abstract · Added February 12, 2015
Protein phosphatase 2A (PP2A) is a ubiquitous phospho-serine/threonine phosphatase that controls many diverse cellular functions. The predominant form of PP2A is a heterotrimeric holoenzyme consisting of a scaffolding A subunit, a variable regulatory B subunit, and a catalytic C subunit. The C subunit also associates with other interacting partners, such as α4, to form non-canonical PP2A complexes. We report visualization of PP2A complexes in mammalian cells. Bimolecular fluorescence complementation (BiFC) analysis of PP2A subunit interactions demonstrates that the B subunit plays a key role in directing the subcellular localization of PP2A, and confirms that the A subunit functions as a scaffold in recruiting the B and C subunits to form a heterotrimeric holoenzyme. BiFC analysis also reveals that α4 promotes formation of the AC core dimer. Furthermore, we demonstrate visualization of specific ABC holoenzymes in cells by combining BiFC and fluorescence resonance energy transfer (BiFC-FRET). Our studies not only provide direct imaging data to support previous biochemical observations on PP2A complexes, but also offer a promising approach for studying the spatiotemporal distribution of individual PP2A complexes in cells.
0 Communities
1 Members
0 Resources
7 MeSH Terms
Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis.
Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W
(2015) Gut 64: 1028-39
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Growth Inhibitors, Immunohistochemistry, Mice, Mice, Knockout, Peptides, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, Stomach Neoplasms, Transcriptional Activation, Trefoil Factor-1, beta Catenin
Show Abstract · Added February 19, 2015
OBJECTIVE - In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-catenin signalling using in vivo and in vitro models of gastric tumorigenesis.
DESIGN - Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on β-catenin signalling pathway.
RESULTS - Nuclear localisation of β-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the β-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of β-catenin in stages of human gastric tumorigenesis.
CONCLUSIONS - Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
0 Communities
2 Members
0 Resources
17 MeSH Terms
High glucose exposure promotes activation of protein phosphatase 2A in rodent islets and INS-1 832/13 β-cells by increasing the posttranslational carboxylmethylation of its catalytic subunit.
Arora DK, Machhadieh B, Matti A, Wadzinski BE, Ramanadham S, Kowluru A
(2014) Endocrinology 155: 380-91
MeSH Terms: Animals, Catalytic Domain, Glucose, Humans, Insulin-Secreting Cells, Islets of Langerhans, Male, Oxidative Stress, Protein Phosphatase 2, Protein Processing, Post-Translational, Rats, Rats, Sprague-Dawley, Signal Transduction
Show Abstract · Added March 26, 2014
Existing evidence implicates regulatory roles for protein phosphatase 2A (PP2A) in a variety of cellular functions, including cytoskeletal remodeling, hormone secretion, and apoptosis. We report here activation of PP2A in normal rat islets and insulin-secreting INS-1 832/13 cells under the duress of hyperglycemic (HG) conditions. Small interfering RNA-mediated knockdown of the catalytic subunit of PP2A (PP2Ac) markedly attenuated glucose-induced activation of PP2A. HG, but not nonmetabolizable 3-O-methyl glucose or mannitol (osmotic control), significantly stimulated the methylation of PP2Ac at its C-terminal Leu-309, suggesting a novel role for this posttranslational modification in glucose-induced activation of PP2A. Moreover, knockdown of the cytosolic leucine carboxymethyl transferase 1 (LCMT1), which carboxymethylates PP2Ac, significantly attenuated PP2A activation under HG conditions. In addition, HG conditions, but not 3-O-methyl glucose or mannitol, markedly increased the expression of LCMT1. Furthermore, HG conditions significantly increased the expression of B55α, a regulatory subunit of PP2A, which has been implicated in islet dysfunction under conditions of oxidative stress and diabetes. Thapsigargin, a known inducer of endoplasmic reticulum stress, failed to exert any discernible effects on the carboxymethylation of PP2Ac, expression of LCMT1 and B55α, or PP2A activity, suggesting no clear role for endoplasmic reticulum stress in HG-induced activation of PP2A. Based on these findings, we conclude that exposure of the islet β-cell to HG leads to accelerated PP2A signaling pathway, leading to loss in glucose-induced insulin secretion.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Protein phosphatase 2A family members (PP2A and PP6) associate with U1 snRNP and the spliceosome during pre-mRNA splicing.
Kamoun M, Filali M, Murray MV, Awasthi S, Wadzinski BE
(2013) Biochem Biophys Res Commun 440: 306-11
MeSH Terms: HEK293 Cells, HeLa Cells, Humans, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, RNA Splicing, Ribonucleoprotein, U1 Small Nuclear, Ribonucleoprotein, U2 Small Nuclear, Spliceosomes, Thymocytes
Show Abstract · Added March 7, 2014
Protein phosphorylation and dephosphorylation are both important for multiple steps in the splicing pathway. Members of the PP1 and PP2A subfamilies of phospho-serine/threonine phosphatases play essential but redundant roles in the second step of the splicing reaction. PP6, a member of the PP2A subfamily, is the mammalian homolog of yeast Sit4p and ppe1, which are involved in cell cycle regulation; however, the involvement of PP6 in the splicing pathway remains unclear. Here we show that PP2A family members physically associate with the spliceosome throughout the splicing reaction. PP2A holoenzyme and PP6 were found stably associated with U1 snRNP. Together our findings indicate that these phosphatases regulate splicing catalysis involving U1 snRNP and suggest an important evolutionary conserved role of PP2A family phosphatases in pre-mRNA splicing.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
PPM1A is a RelA phosphatase with tumor suppressor-like activity.
Lu X, An H, Jin R, Zou M, Guo Y, Su PF, Liu D, Shyr Y, Yarbrough WG
(2014) Oncogene 33: 2918-27
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Cell Nucleus, Chemokine CCL2, Disease Models, Animal, Gene Expression, Heterografts, Humans, Male, Mice, NF-kappa B, Neoplasm Metastasis, Phosphoprotein Phosphatases, Phosphorylation, Prostatic Neoplasms, Protein Binding, Protein Phosphatase 2C, Protein Transport, Transcription Factor RelA, Transcription, Genetic, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins
Show Abstract · Added March 10, 2014
Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-κB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-κB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony metastases in human cancer.
0 Communities
3 Members
0 Resources
23 MeSH Terms
Structural basis of protein phosphatase 2A stable latency.
Jiang L, Stanevich V, Satyshur KA, Kong M, Watkins GR, Wadzinski BE, Sengupta R, Xing Y
(2013) Nat Commun 4: 1699
MeSH Terms: Catalytic Domain, Crystallization, Enzyme Stability, Models, Molecular, Protein Conformation, Protein Phosphatase 2, Ubiquitination
Show Abstract · Added March 26, 2014
The catalytic subunit of protein phosphatase 2A (PP2Ac) is stabilized in a latent form by α4, a regulatory protein essential for cell survival and biogenesis of all PP2A complexes. Here we report the structure of α4 bound to the N-terminal fragment of PP2Ac. This structure suggests that α4 binding to the full-length PP2Ac requires local unfolding near the active site, which perturbs the scaffold subunit binding site at the opposite surface via allosteric relay. These changes stabilize an inactive conformation of PP2Ac and convert oligomeric PP2A complexes to the α4 complex upon perturbation of the active site. The PP2Ac-α4 interface is essential for cell survival and sterically hinders a PP2A ubiquitination site, important for the stability of cellular PP2Ac. Our results show that α4 is a scavenger chaperone that binds to and stabilizes partially folded PP2Ac for stable latency, and reveal a mechanism by which α4 regulates cell survival, and biogenesis and surveillance of PP2A holoenzymes.
0 Communities
1 Members
0 Resources
7 MeSH Terms
Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation.
Watkins GR, Wang N, Mazalouskas MD, Gomez RJ, Guthrie CR, Kraemer BC, Schweiger S, Spiller BW, Wadzinski BE
(2012) J Biol Chem 287: 24207-15
MeSH Terms: Blotting, Western, Cell Line, Humans, Immunoprecipitation, Mass Spectrometry, Microtubule-Associated Proteins, Phosphorylation, Protein Phosphatase 2, Protein Stability, Ubiquitination
Show Abstract · Added March 26, 2014
Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Protein phosphatase 2A (PP2A) is the major MAP phosphatase; however, little is known about its regulation at microtubules. α4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved α4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of α4, and dysregulation of α4 cleavage may contribute to Opitz syndrome and Alzheimer disease.
0 Communities
2 Members
0 Resources
10 MeSH Terms