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

G A Finlay1, D S Hunter, C L Walker

  • 1Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, New England Medical Center, NEMC #257, 750 Washington St., Boston, MA 02111, USA. gfinlay@tufts-nemc.org

American Journal of Physiology. Cell Physiology
|April 18, 2003
PubMed

Insights

Estrogen

Area of Science:

  • Cell Biology
  • Endocrinology
  • Molecular Biology

Background:

  • Mechanisms regulating estrogen's growth effects are unclear.
  • Tuberous sclerosis complex 2 (TSC2) gene loss links to estrogen-related proliferation.
  • Vascular smooth muscle cells (VSMCs) are key in estrogen response.

Purpose of the Study:

  • Investigate estrogen's differential effects on VSMCs with and without TSC2.
  • Elucidate the role of TSC2 in mediating estrogen-induced cell growth.
  • Identify signaling pathways involved in estrogen-driven proliferation.

Main Methods:

  • Compared E2 response in wild-type TSC2 VSMCs and TSC2-null ELT-3 cells.
  • Analyzed expression of platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR).
  • Assessed extracellular signal-regulated kinase (ERK) pathway activation via phosphorylation.
  • Utilized PDGFR inhibitor (tyrphostin AG 17) and PDGF-neutralizing antibody.

Main Results:

  • Estrogen inhibited growth in TSC2-expressing VSMCs, downregulating PDGF/PDGFR and limiting ERK activation.
  • Estrogen promoted growth in TSC2-null ELT-3 cells, inducing PDGF, robust PDGFR phosphorylation, and sustained ERK activation.
  • PDGF autocrine signaling and ERK pathway activation mediated estrogen-induced proliferation in TSC2-null cells.
  • Inhibition of PDGFR or PDGF blocked E2-induced growth and ERK activation in ELT-3 cells.

Conclusions:

  • TSC2 regulates estrogen's effect on VSMC growth by modulating PDGF/ERK signaling.
  • Autocrine PDGF signaling and ERK activation drive estrogen-induced proliferation in TSC2-deficient cells.
  • Understanding these pathways may offer new treatments for estrogen-related proliferative diseases.

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