Gn. Rao et Ms. Runge, CYCLIC-AMP INHIBITION OF THROMBIN-INDUCED GROWTH IN VASCULAR SMOOTH-MUSCLE CELLS CORRELATES WITH DECREASED JNK1 ACTIVITY AND C-JUN EXPRESSION, The Journal of biological chemistry, 271(34), 1996, pp. 20805-20810
Thrombin is a potent modulator of vascular tone and vascular smooth mu
scle cell (VSMC) mitogenesis. Early studies from other laboratories de
monstrated that cyclic AMP (cAMP) antagonizes the mitogenic effects of
platelet-derived growth factor and epidermal growth factor by inhibit
ing the extracellular signal-regulated protein kinases (ERKs; p42, p44
) group of mitogen-activated protein kinases (MAPKs) in several cell t
ypes. This report examines the role of ERKs and Jun N-terminal kinase
1 (JNK1) groups of mitogen-activated protein kinases in thrombin-induc
ed DNA synthesis in VSMCs using agents such as forskolin and dibutyryl
cyclic AMP that increase intracellular cAMP levels, Both agents signif
icantly inhibited thrombin-stimulated DNA synthesis in VSMCs, These ag
ents, however, had no effect on thrombin induction of ERKs activation
and c-Fos expression, suggesting divergence of the latter two events f
rom the growth-signaling events of thrombin that are sensitive to inhi
bition by cAMP. Thrombin activated JNK1 and induced c-Jun expression i
n VSMCs in a time-dependent manner, In contrast to ERKs and c-Fos, thr
ombin-induced JNK1 activation and c-Jun expression were sensitive to i
nhibition by forskolin, suggesting an association of these events with
thrombin-stimulated growth in these cells, Thrombin also increased AP
-1 activity, and this response was significantly blunted by forskolin,
Together, these results demonstrate a correlation between JNK1 activa
tion and c-Jun expression by thrombin and their association with the m
itogenic signaling events of thrombin in VSMCs.