The mitogenic inhibitory effect of phorbol esters is associated
with decreased activation of phosphatidylinositol-3 kinase.
Weiss, Robert H., and Ann P. Yabes.
Division of Nephrology, Department of Internal Medicine, University
of California, Davis, CA. 95616 and Department of Veteran's Affairs
Northern California System of Clinics, Pleasant Hill, CA. 94523
APStracts 2:0320C, 1995.
In contrast to their role as potent tumor promoters, phorbol esters
can cause inhibition of cell growth. Since the effect of phorbol
esters occurs through activation of protein kinase C (PKC), and
because activated PKC is translocated to the membrane placing it in a
position to act on the intracellular portion of the growth factor
receptor, we asked whether this inhibitory effect is mediated through
the action of phorbol-12-myristate-13-acetate (PMA) on receptor
association with the signal transfer proteins. When added to rat
vascular smooth muscle (VSM) cells concurrently with bFGF, PMA at 100
ng/ml completely inhibits bFGF-stimulated DNA synthesis. Under the
same growth-inhibitory conditions of PMA addition, aggregation of
phosphatidylinositol-3 kinase (PI3K) to the FGF receptor and tyrosine
phosphorylation of the 85 kD regulatory component of the signal
transfer protein PI3K are reduced by 94% and 79%, respectively. PI3K
catalytic activity, as measured by conversion of phosphatidylinositol
to phosphatidylinositol monophosphate, is decreased 88% by PMA
addition. This effect is not specific to PI3K, as aggregation of PLC
-[gamma]1 to the activated bFGF receptor is also decreased by PMA
treatment. In addition, the PI3K inhibitor wortmannin markedly
attenuates bFGF-stimulated VSM cell growth in a dose-dependent
manner. These data suggest that the site of growth inhibition by PMA
in vascular smooth muscle cells lies upstream of signal transfer
particle aggregation and that such growth arrest may be mediated
through inhibition of activation of PI3K.
Received 5 July 1995; accepted in final form 28 August 1995.
APS Manuscript Number C402-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.