The elucidation of the roles of cell-adhesion molecules in heart diseases

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In response to hypoxia and reoxygenation, mammalian cells are known to express a variety of genes to adapt to these external stresses or lead to further cell damage. The intracellular signaling cascades in cultured rat cardiac myocytes subjected to hypoxia or hypoxia followed by reoxygenation (hypoxia/reoxygenation) were investigated. We showed that both hypoxia and hypoxia/reoxygenation cause rapid activation of the mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. The activation was followed by the sequential activation of mitogen-activated protein kinase kinase (MAPKK), mitogen-activated protein (MAP) kinases, and S6 kinase (p90^<rsk>). Furthermore, hypoxia caused hyperphosphorylation of Raf-1. The maximal hyperphosphorylation of Raf-1 appeared to be accompanied by a significant decrease in MAPKKK activity. These results strongly suggest the following : (1) intracellular signals initiated by both hypoxia and hypoxia/reoxygenation converge on Raf-1, which sequentially activates downstream serine/threonine kinases including MAPKK,MAP kinases, and p90^<rsk>, (2) Raf-1 is not only located upstream from MAPKK and MAP kinases but also may be phosphorylated by MAP kinases directly or indirectly, and at least Raf-1 kinase activity may be downregulated by this feedback mechanism.