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PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D
F J Sulzmaier1, M K G Valmiki, D A Nelson
1Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
Oncogene
|November 23, 2011
Summary
Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) surprisingly enhances Ras/ERK signaling and tumor growth in H-Ras-transformed cells. This occurs via phospholipase D1 (PLD1) activation, revealing a novel pro-tumorigenic role for PEA-15.
Area of Science:
- Molecular biology
- Cell signaling
- Oncology
Background:
- H-Ras is a proto-oncogene frequently mutated in human cancers, driving proliferation via pathways like ERK/MAPK.
- Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) typically inhibits proliferation by sequestering ERK in the cytoplasm.
Purpose of the Study:
- To investigate the role of PEA-15 in H-Ras-mediated cellular transformation.
- To elucidate the molecular mechanisms underlying PEA-15's influence on Ras/ERK signaling.
Main Methods:
- Co-expression of H-Ras and PEA-15 in mouse kidney epithelial cells.
- Assays for soft agar colony growth and in vivo tumor growth.
- Analysis of cell cycle progression (G1/S transition) and ERK signaling pathway activation.
- Investigation of the role of phospholipase D1 (PLD1) and PEA-15/PLD1 interaction.
Main Results:
- PEA-15 did not inhibit proliferation in constitutively active H-Ras transformed cells.
- PEA-15 co-expression enhanced soft agar colony growth and in vivo tumor growth.
- Overexpression of H-Ras and PEA-15 accelerated G1/S cell cycle transition and increased ERK activation.
- PEA-15 mediated these effects via activation of PLD1; PLD1 inhibition blocked PEA-15's pro-proliferative effects.
Conclusions:
- PEA-15 positively regulates Ras/ERK signaling and proliferation in H-Ras-transformed cells.
- PEA-15 enhances H-Ras-driven tumorigenesis through PLD1 activation.
- PEA-15 exhibits context-dependent roles, capable of both suppressing and enhancing tumorigenesis.
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