Abstract |
Protein phosphatase 2A (PP2A) negatively regulates tumorigenic signaling pathways, in part, by supporting the function of tumor suppressors like p53. The PP2A methylesterase PME-1 limits the activity of PP2A by demethylating its catalytic subunit. Here, we report the finding that PME-1 overexpression correlates with increased cell proliferation and invasive phenotypes in endometrial adenocarcinoma cells, where it helps maintain activated ERK and Akt by inhibiting PP2A. We obtained evidence that PME-1 could bind and regulate protein phosphatase 4 (PP4), a tumor-promoting protein, but not the related protein phosphatase 6 (PP6). When the PP2A, PP4, or PP6 catalytic subunits were overexpressed, inhibiting PME-1 was sufficient to limit cell proliferation. In clinical specimens of endometrial adenocarcinoma, PME-1 levels were increased and we found that PME-1 overexpression was sufficient to drive tumor growth in a xenograft model of the disease. Our findings identify PME-1 as a modifier of malignant development and suggest its candidacy as a diagnostic marker and as a therapeutic target in endometrial cancer.
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Authors | Ewa Wandzioch, Michelle Pusey, Amy Werda, Sophie Bail, Aishwarya Bhaskar, Mariya Nestor, Jing-Jing Yang, Lyndi M Rice |
Journal | Cancer research
(Cancer Res)
Vol. 74
Issue 16
Pg. 4295-305
(Aug 15 2014)
ISSN: 1538-7445 [Electronic] United States |
PMID | 24928782
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Carboxylic Ester Hydrolases
- protein phosphatase methylesterase-1
- Protein Phosphatase 2
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Topics |
- Animals
- Carboxylic Ester Hydrolases
(genetics, metabolism)
- Cell Growth Processes
(physiology)
- Endometrial Neoplasms
(enzymology, genetics)
- Female
- Heterografts
- Humans
- Methylation
- Mice
- Mice, Nude
- Phenotype
- Protein Phosphatase 2
(metabolism)
- Signal Transduction
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