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KMID : 0617220030140010201
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Duksung Bulletin Phamaceutical Sciences
2003 Volume.14 No. 1 p.201 ~ p.208
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p38 Kinase Is a Key Signaling Molecule for H-Ras-induced Cell Motility and Invasive Phenotype in Human Breast Epithelial Cells^(1)
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Kim, Mi-Sung
Lee, Eun-Jung/Choi Kim, Hyeong-Reh/Moon, Aree
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Abstract
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Ras expression has been suggested as a marker for tumor aggressiveness of breast cancer, including the degrees of invasion and tumor recurrence. We showed previously that H-ras, but not N-ras, up-regulates matrix metalloproteinase 2 expression and induces invasive phenotype in MCF10A human breast epithelial cells (A. Moon, et al. Int. J. Cancer, 85: 176-181, 2000). In this study, we show that H-ras also promotes cell motility more effectively than N-ras in MCF10A cells. We have investigated H-ras-specific signaling pathway(s) critical for H-ras-mediated cell motility and invasive phenotype. Whereas neither H-ras nor N-ras activated c-Jun NH_(2)-terminal kinase 1, both H-ras and N-ras effectively activated extracellular signal-regulated protein kinase (ERK)-1,2. Importantly, prominent activation of p38 mitogen-activated cells but not in N-ras activated MCF10A cells. Functional significance of H-ras activated p38 in invasiveness and cell motility was evidenced by studies using SB203580, a chemical inhibitor of p38, and a dominant-negative construct of p38. Whereas inhibition of c-Jun NH_(2)-terminal kinase 1 activity had noeffect on H-ras induced MCF10A cell invasion and motility, the inhibition of the ERK pathway using a chemical inhibitor PD98059 or dominant-negative mutant of mitogen-activated protein/ERK kinase 1, an activator of ERKs, significantly reduced H-ras-induced invasion and migration. We also provide evidence that p38 and, to a lesser degree, ERKs, are critical for H-ras-mediated up-regulation of matrix metalloproteinase 2. Taken together, the present study shows that H-ras activation of both p38 and ERKs induces cell invasion and motility, whereas N-ras activation of ERKs alone is not sufficient. This study reveals the p38 kinase as a key signaling molecule differentially regulated by H-ras and N-ras, leading to H-ras-specific cell invasive and migrative phenotypes in human breast epithelial cells.
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KEYWORD
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