期刊
CANCER RESEARCH
卷 69, 期 7, 页码 2870-2877出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-2760
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资金
- Academy of Finland [1121413]
- Pirkanmaa Hospital District [9J151]
- Emil Aaltonen Foundation
- Helsinki University Central Hospital Research Funds
- Sigrid Juselius Foundation
- Finnish Cancer Society
- Damon Runyon Cancer Research Foundation
Extracellular signal-regulated kinase (ERR)/mitogen-activated protein kinase pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies; however, the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here, we show that methylesterase PME-1-mediated inhibition of the protein phosphatase 2A promotes basal ERK pathway activity and is required for efficient growth factor response. Mechanistically, PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and protein kinase C. In malignant gliomas, PME-1 expression levels correlate with both ERR activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (n = 222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells and suggest an important functional role for PME-1 in the disease progression of human astrocytic gliomas. [Cancer Res 2009;69(7):2870-7]
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