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Identification of PP2A complexes and pathways involved in cell transformation.

ABSTRACT: The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine-threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56?, B56?, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56?, B56?, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation.

SUBMITTER: Sablina AA

PROVIDER: S-EPMC3056544 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Identification of PP2A complexes and pathways involved in cell transformation.

Sablina Anna A AA Hector Melissa M Colpaert Nathalie N Hahn William C WC

Cancer research 20101201 24

The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine-threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 ...[more]

PMID: 21159657

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Project description:BackgroundThe immunopathogenesis of chronic spontaneous urticaria (CSU) is poorly understood, but recent research suggests that patients can be divided into autoallergic and autoimmune subtypes. Given that not all patients can be controlled with current treatment regimens, including anti-IgE monoclonal antibodies, a better understanding of the immune pathways involved in CSU may enable the repurposing of monoclonal antibodies used for other dermatologic diseases (e.g., Th2 and Th17 inhibitors). Therefore, we investigated the implicated immune cells and pathways by reanalyzing publicly available transcriptomic data.MethodsMicroarray data of CSU and healthy control (HC) skin and blood were obtained from the Gene Expression Omnibus (GSE72542, GSE57178). Differentially expressed genes were defined as a false discovery rate <0.05 and a |log2 fold change| ≥1. Pathway analyses were conducted using ToppGene and KEGG. Cell-type enrichment was determined by CIBERSORT and xCell and was correlated with clinical characteristics.ResultsTh2 (IL-4/13 signaling) and Th17-related (IL-17/23 signaling) pathways were upregulated in lesional compared to non-lesional and HC samples. In non-lesional versus lesional samples, CIBERSORT analysis revealed increased regulatory T-cells (Treg) and resting mast cells. xCell analysis established that Th1 and Th2 scores were not significantly different between lesional and HC samples. However, Th2 scores in both lesional and non-lesional samples correlated positively with disease severity. Few differentially expressed genes and pathways were identified between CSU and HC blood samples.ConclusionOur results support the involvement of Th2 and Th17-related genes and pathways in CSU. Th2 scores associate with disease severity, which indicates the clinical relevance of these findings. Increased resting mast cell and Treg scores in non-lesional samples may suggest local suppression of wheal formation. Moreover, disease activity seemed to be restricted to the skin as there were limited findings from blood. Larger studies using next-generation sequencing will be helpful to confirm these results.

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Identification of PP2A complexes and pathways involved in cell transformation.

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Identification of PP2A complexes and pathways involved in cell transformation.

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