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RECEPTORS AND SIGNAL TRANSDUCTION

Regulation of PDGF production and ERK activation by estrogen is associated with TSC2 gene expression

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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