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RECEPTORS AND SIGNAL TRANSDUCTION
1Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, New England Medical Center, Boston, Massachusetts 02111; 2Department of Carcinogenesis, University of Texas, M. D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957; and 3Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111
Submitted 16 October 2002 ; accepted in final form 9 April 2003
Mechanisms that regulate the growth response to estrogen
(17
-estradiol, E2) are poorly understood. Recently, loss of
function of the tuberous sclerosis complex 2 (TSC2) gene has been
associated with E2-related conditions that are characterized by
benign cellular proliferation. We examined the growth response to
E2 in vascular smooth muscle cells (VSMCs) that possess wild-type
TSC2 and compared them with ELT-3 smooth muscle cells that do not
express TSC2.In TSC2-expressing VSMCs, growth inhibition in
response to E2 was associated with downregulation of
platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), and limited
activation of extracellular signal-regulated kinase (ERK). In contrast, the
growth-promoting effect of E2 in TSC2-null ELT-3 cells was
associated with induction of PDGF, robust phosphorylation of PDGFR, and
sustained activation of ERK. Furthermore, in ELT-3 cells, cellular growth and
ERK activation by E2 were inhibited by the PDGFR inhibitor
tyrphostin AG 17 and by PDGF-neutralizing antibody. These results demonstrate
that autocrine production of PDGF and augmentation of the ERK pathway leads to
estrogen-induced cellular proliferation in TSC2-null cells, a pathway
that was downregulated in cells that express TSC2. Understanding the
mechanisms that regulate the diverse responses to the steroid hormone estrogen
could lead to novel approaches to the treatment of estrogen-related diseases
that are characterized by aberrant cell proliferation.
tuberous sclerosis complex 2 gene; tuberin; cell growth; mitogen-activated protein kinase
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