scholarly journals Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways

Cell Cycle ◽  
2012 ◽  
Vol 11 (3) ◽  
pp. 451-459 ◽  
Author(s):  
Gernot Walter ◽  
Ralf Ruediger
Keyword(s):  
Tumor Suppressor ◽  
Mouse Model ◽  
Signaling Pathways ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Phosphatase 2A

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.

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.

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

scholarly journals Structural basis for PTPA interaction with the invariant C-terminal tail of PP2A

2014 ◽  
Vol 395 (7-8) ◽  
pp. 881-889 ◽  
Author(s):  
Christian Löw ◽  
Esben M. Quistgaard ◽  
Michael Kovermann ◽  
Madhanagopal Anandapadamanaban ◽  
Jochen Balbach ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Posttranslational Modifications ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Catalytic Subunit ◽  
Structural Basis ◽  
Interaction Site ◽  
Interaction Partners ◽  
Phosphatase 2A ◽  
Additional Interaction

Abstract Protein phosphatase 2A (PP2A) is a highly abundant heterotrimeric Ser/Thr phosphatase involved in the regulation of a variety of signaling pathways. The PP2A phosphatase activator (PTPA) is an ATP-dependent activation chaperone, which plays a key role in the biogenesis of active PP2A. The C-terminal tail of the catalytic subunit of PP2A is highly conserved and can undergo a number of posttranslational modifications that serve to regulate the function of PP2A. Here we have studied structurally the interaction of PTPA with the conserved C-terminal tail of the catalytic subunit carrying different posttranslational modifications. We have identified an additional interaction site for the invariant C-terminal tail of the catalytic subunit on PTPA, which can be modulated via posttranslational modifications. We show that phosphorylation of Tyr307PP2A-C or carboxymethylation of Leu309PP2A-C abrogates or diminishes binding of the C-terminal tail, whereas phosphorylation of Thr304PP2A-C is of no consequence. We suggest that the invariant C-terminal residues of the catalytic subunit can act as affinity enhancer for different PP2A interaction partners, including PTPA, and a different ‘code’ of posttranslational modifications can favour interactions to one subunit over others.

Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer

10.1038/ng747 ◽  
2001 ◽  
Vol 29 (4) ◽  
pp. 418-425 ◽  
Author(s):  
Jos Jonkers ◽  
Ralph Meuwissen ◽  
Hanneke van der Gulden ◽  
Hans Peterse ◽  
Martin van der Valk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Mouse Model ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Conditional Mouse Model

scholarly journals Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53

2013 ◽  
Vol 35 (1) ◽  
pp. 114-122 ◽  
Author(s):  
François H.T. Duong ◽  
Michael T. Dill ◽  
Matthias S. Matter ◽  
Zuzanna Makowska ◽  
Diego Calabrese ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Hepatocellular Carcinogenesis ◽  
Phosphatase 2A
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