Protein phosphatase 2A: the Trojan Horse of cellular signaling

Sontag, Estelle

doi:10.1016/s0898-6568(00)00123-6

Cited by 310 publications

(300 citation statements)

References 126 publications

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“…As reported above, the tumour-suppressing activity of PP2A depends on its ability to dephosphorylate several factors regulating cell cycle progression, proliferation, survival and differentiation (Sontag, 2001). Remarkably, several targets are shared by BCR/ ABL kinase and PP2A phosphatase.…”

Section: Adverse Molecular Effects Of Bcr/abl and Pp2amentioning

confidence: 77%

“…PP2A is involved in almost all of the cellular processes, including signal-transduction pathways transducing mitogenic and survival signals (e.g. PP2A negatively regulates the RAS/MAPK and the PI3K/Akt pathways), transcriptional and translational regulation, DNA replication and control of cell cycle (Janssens and Goris, 2001;Sontag, 2001).…”

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

“…For example, genetic alterations of the genes encoding the b-isoform of the structural subunit PP2A A and some of the regulatory PP2A B subunits have been found in several types of human cancer Janssens et al, 2005, and references therein). Moreover, oncogenic viral proteins, such as the SV40 virus small-t antigen, inhibit PP2A activity by interacting with the subunit A of PP2A complexes and displacing various B subunits (Sontag, 2001). Conversely, overexpression of PP2Ac reduces Ha-RAS-induced cellular transformation (Baharians and Schonthal, 1999).…”

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

“…MAPK and AKT) and protoncogenes (e.g. Myc) (Sontag, 2001;Yuan et al, 2002;Yeh et al, 2004). Furthermore, the PP2A subunit A per se also has been described to be genetically or functionally altered in different types of cancer.…”

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

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ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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Section: Adverse Molecular Effects Of Bcr/abl and Pp2amentioning

confidence: 77%

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

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ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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“…The impact of these maladaptive changes in the brain is profound considering that PP2A is the master regulator of the cellular phospho‐regulatory network and plays key roles in regulating cytoskeletal integrity and signal transduction 26, 27, 28. Considering the deleterious consequences of a dysfunctional PP2A, it is unlikely that the changes observed in these postmortem brain analyses represent a protective effect in surviving neurons.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Park

Lee

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProtein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.MethodsWe compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.Results LCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.InterpretationThese findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.

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Bad Protein, a BH 3‐only Member of the BCL ‐2 Family

Hardwick

2002

Wiley Encyclopedia of Molecular Medicine

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Protein phosphatase 2A: the Trojan Horse of cellular signaling

Cited by 310 publications

References 126 publications

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Bad Protein, a BH 3‐only Member of the BCL ‐2 Family

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