Abstract
Mechanisms that regulate the growth response to estrogen (17beta-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autocrine Communication / drug effects
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Autocrine Communication / genetics
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Cell Division / drug effects
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Cell Division / physiology*
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology*
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Endothelium, Vascular / growth & development*
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Estrogens / metabolism*
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Estrogens / pharmacology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Mice
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism
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Models, Biological
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Muscle, Smooth / drug effects
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Muscle, Smooth / enzymology*
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Muscle, Smooth / growth & development*
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Nitriles
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Phosphorylation / drug effects
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Platelet-Derived Growth Factor / drug effects
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Platelet-Derived Growth Factor / metabolism
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Rats
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Tuberous Sclerosis Complex 2 Protein
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
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Tyrphostins / pharmacology
Substances
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Estrogens
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Nitriles
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Platelet-Derived Growth Factor
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Repressor Proteins
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Tsc2 protein, mouse
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Tsc2 protein, rat
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Tyrphostins
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SF 6847
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Receptor, Platelet-Derived Growth Factor beta
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Mitogen-Activated Protein Kinases