HYPOXIA AND HYPOXIA REOXYGENATION ACTIVATE SRC FAMILY TYROSINE KINASES AND P21(RAS) IN CULTURED RAT CARDIAC MYOCYTES/

We previously reported that both hypoxia and hypoxia followed by reoxy genation (hypoxia/reoxygenation) rapidly and sequentially activate mit ogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1 . This was followed by the sequential activation of MAP kinase kinase (MAPKK), MAP kinases (p42(mapk) and p44(mapk)), and S6 kinase (p90(rsk )). In this study, we demonstrated that both hypoxia and hypoxia/reoxy genation caused rapid activation of Src family tyrosine kinases, p60(c -src) and p59(c-fyn), which are upstream mediators of MAP kinase activ ation. This was followed by the activation of p21(ras). Because Src fa mily tyrosine kinases are known to be cell-surface-associated kinases and upstream regulators of p21(ras), these results strongly suggested that activation of Src family tyrosine kinases plays a key role in tri ggering intracellular signaling cascades in cardiac myocytes in respon se to hypoxia and hypoxia/reoxygenation. (C) 1996 Academic Press, Inc.