Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-β and ERK-1/2
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Finlay, GA
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
Finlay, GA
York, B
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
York, B
Karas, RH
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
Karas, RH
Fanburg, BL
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
Fanburg, BL
Zhang, HB
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
Zhang, HB
Kwiatkowski, DJ
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
Kwiatkowski, DJ
Noonan, DJ
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机构:Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
Noonan, DJ
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[1] Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Div Pulm & Crit Care, Boston, MA 02111 USA
[2] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA
[3] Tufts Univ New England Med Ctr, Tupper Res Inst, Dept Med, Mol Cardiol Res Inst, Boston, MA 02111 USA
[4] Brigham & Womens Hosp, Longwood Med Res Inst, Boston, MA 02111 USA
The mechanisms that regulate the diverse responses to estrogen (E-2) are unknown. Loss of function of the tuberous sclerosis 2 gene (TSC2), a tumor suppressor gene, has been associated with a growth-promoting effect of E-2. We hypothesized that tuberin, the protein product of TSC2, binds to estrogen receptors ( ER) and regulates the growth effect of E-2. An in vivo association between full-length tuberin and ERalpha was observed in HEK 293 cells and ELT-3 smooth muscle cells. In contrast, poor association was observed between tuberin and ERbeta. Complex formation with ERalpha and the C-terminal end of tuberin was also observed in vivo and in vitro, indicating that binding between ERalpha and tuberin occurs at the C-terminal end of the tuberin molecule. We examined the effect of tuberin expression in ELT-3 smooth muscle cells on the growth response to E-2. The growth-promoting effect of E-2 in tuberin-null ELT-3 smooth muscle cells was ERalpha-specific, associated with up-regulation and activation of platelet-derived growth factor receptor-beta (PDGFRbeta) and activation of the signaling intermediate, extracellular signal-regulated kinase-1/-2 (ERK-1/ 2). In contrast, the expression of tuberin in ELT-3 smooth muscle cells resulted in significant abrogation of E-2-stimulated growth. In parallel with this observation, the expression of tuberin in ELT-3 cells also resulted in significant inhibition of PDGFRbeta and ERK-1/ 2 activation in response to E-2. These results demonstrate that tuberin binds specifically to ERalpha and inhibits E-2-induced proliferation of ELT-3 cells. Furthermore, the opposing effects of tuberin on estrogen-induced activation of PDGFRbeta and ERK-1/-2 suggest a pivotal role for tuberin in directing the signaling events that dictate the growth response to E-2.
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
FARHAT, MY
VARGAS, R
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
VARGAS, R
DINGAAN, B
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
DINGAAN, B
RAMWELL, PW
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
机构:
GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
FARHAT, MY
VARGAS, R
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
VARGAS, R
DINGAAN, B
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA
DINGAAN, B
RAMWELL, PW
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GEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USAGEORGETOWN UNIV, MED CTR, DEPT PHYSIOL & BIOPHYS, WASHINGTON, DC 20007 USA