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Am J Physiol Cell Physiol (April 16, 2003). doi:10.1152/ajpcell.00482.2002
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Submitted on October 16, 2002
Accepted on April 9, 2003

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

G A Finlay1*, D S Hunter2, C L Walker2, K E Paulson3, and B L Fanburg1

1 Pulmonary and Critical Care Division, Tupper Research Institute, New England Medical Center, Boston, Massachusetts, USA
2 Department of Carcinogenesis, M.D. Anderson Cancer Center, University of Texas, Smithville, Texas, USA
3 Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, USA

* To whom correspondence should be addressed. E-mail: gfinlay{at}tufts-nemc.org.

Mechanisms that regulate the growth response to estrogen (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 (VSMC) which possess wild-type TSC2, and compared them to 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), platelet derived growth factor receptor (PDGFR) and limited activation of ERK. In contrast, the growth-promoting effect of E2 in TSC2 null ELT-3 cells was associated with induction of PDGF, robust phosphorylation of PDGF receptor (PDGFR) and sustained activation of ERK. Furthermore, in ELT-3 cells, cellular growth and ERK activation by E2 were inhibited by the PDGFR inhibitor, AG17, and by PDGF-neutralizing antibody. These results demonstrate that the 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.




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