Regulation of protein phosphatase 2A (PP2A) tumor suppressor function by PME-1

2016 ◽  
Vol 44 (6) ◽  
pp. 1683-1693 ◽  
Author(s):  
Amanpreet Kaur ◽  
Jukka Westermarck
Keyword(s):  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Kinase Inhibitor ◽  
Protein Phosphatase 2A ◽  
Signaling Proteins ◽  
Tumor Suppressor Function ◽  
Phosphatase 2A ◽  
Cancer Types ◽  
Associated Function ◽  
Inhibitor Resistance

Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis by dephosphorylation of a variety of signaling proteins and acts as a tumor suppressor. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by highly complex mechanisms that are reviewed here. Importantly, recent studies have shown that PME-1 promotes oncogenic MAPK/ERK and AKT pathway activities in various cancer types. In human glioma, high PME-1 expression correlates with tumor progression and kinase inhibitor resistance. We discuss the emerging cancer-associated function of PME-1 and its potential clinical relevance.

scholarly journals Protein Phosphatase 2A Regulatory Subunit B56α Associates with c-Myc and Negatively Regulates c-Myc Accumulation

2006 ◽  
Vol 26 (7) ◽  
pp. 2832-2844 ◽  
Author(s):  
Hugh K. Arnold ◽  
Rosalie C. Sears
Keyword(s):  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Cell Function ◽  
Cell Transformation ◽  
Protein Phosphatase 2A ◽  
Regulatory Subunit ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Structural Subunit ◽  
Phosphatase 2A

ABSTRACT Protein phosphatase 2A (PP2A) plays a prominent role in controlling accumulation of the proto-oncoprotein c-Myc. PP2A mediates its effects on c-Myc by dephosphorylating a conserved residue that normally stabilizes c-Myc, and in this way, PP2A enhances c-Myc ubiquitin-mediated degradation. Stringent regulation of c-Myc levels is essential for normal cell function, as c-Myc overexpression can lead to cell transformation. Conversely, PP2A has tumor suppressor activity. Uncovering relevant PP2A holoenzymes for a particular target has been limited by the fact that cellular PP2A represents a large heterogeneous population of trimeric holoenzymes, composed of a conserved catalytic subunit and a structural subunit along with a variable regulatory subunit which directs the holoenzyme to a specific target. We now report the identification of a specific PP2A regulatory subunit, B56α, that selectively associates with the N terminus of c-Myc. B56α directs intact PP2A holoenzymes to c-Myc, resulting in a dramatic reduction in c-Myc levels. Inhibition of PP2A-B56α holoenzymes, using small hairpin RNA to knock down B56α, results in c-Myc overexpression, elevated levels of c-Myc serine 62 phosphorylation, and increased c-Myc function. These results uncover a new protein involved in regulating c-Myc expression and reveal a critical interconnection between a potent oncoprotein, c-Myc, and a well-documented tumor suppressor, PP2A.

Protein phosphatase 2A is essential to maintain active Wnt signaling and its Aβ tumor suppressor subunit is not expressed in colon cancer cells

2014 ◽  
Vol 54 (11) ◽  
pp. 1430-1441 ◽  
Author(s):  
M. Carmen Figueroa-Aldariz ◽  
M. Cristina Castañeda-Patlán ◽  
Paula Santoyo-Ramos ◽  
Alejandro Zentella ◽  
Martha Robles-Flores
Keyword(s):  
Colon Cancer ◽  
Tumor Suppressor ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Colon Cancer Cells ◽  
Phosphatase 2A

Potential role for inhibition of protein phosphatase 2A tumor suppressor in salivary gland malignancies

2015 ◽  
Vol 55 (1) ◽  
pp. 69-81 ◽  
Author(s):  
Johannes Routila ◽  
Juho-Antti Mäkelä ◽  
Heikki Luukkaa ◽  
Ilmo Leivo ◽  
Heikki Irjala ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Potential Role ◽  
Protein Phosphatase 2A ◽  
Phosphatase 2A

scholarly journals Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

2019 ◽  
Author(s):  
Joni Merisaari ◽  
Oxana V. Denisova ◽  
Milena Doroszko ◽  
Vadim Le Joncour ◽  
Patrik Johansson ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Oral Dosing ◽  
Phosphatase 2A ◽  
Genetic Mechanisms ◽  
Primary Glioma ◽  
Inhibitor Resistance

AbstractGlioblastoma (GB) is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumor suppressors has not been thoroughly studied as yet as a GB therapeutic strategy. Tumor suppressor Protein Phosphatase 2A (PP2A), is inhibited by non-genetic mechanisms in GB, and thus it would be potentially amendable for therapeutic reactivation. Here we demonstrate, that small molecule activators of PP2A (SMAPs), NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier (BBB), and in vivo partition to mouse brain tissue after oral dosing. In vitro, SMAPs exhibit robust cell killing activity against five established GB cell lines, and nine patient-derived primary glioma cell lines. Collectively these cell lines have heterogenous genetic background, kinase inhibitor resistance profile, and stemness properties; and they represent different clinical GB subtypes. Oral dosing of either of the SMAPs significantly reduced growth of infiltrative intracranial GB tumors. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested GB cell lines, also significantly increased survival of mice bearing orthotopic GB xenografts. In summary, this report presents a proof-of-principle data for BBB-permeable tumor suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background.

scholarly journals Serine 15 Phosphorylation of p53 Directs Its Interaction with B56γ and the Tumor Suppressor Activity of B56γ-Specific Protein Phosphatase 2A

2007 ◽  
Vol 28 (1) ◽  
pp. 448-456 ◽  
Author(s):  
Geoffrey P. Shouse ◽  
Xin Cai ◽  
Xuan Liu
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Specific Protein ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Phosphatase 2A ◽  
Tumor Suppressive Function

ABSTRACT Earlier studies have demonstrated a functional link between B56γ-specific protein phosphatase 2A (B56γ-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56γ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56γ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56γ3-induced inhibition of cell proliferation, induction of cell cycle arrest in G1, and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56γ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56γ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56γ-PP2A.

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