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

被引:55
作者
Finlay, GA
York, B
Karas, RH
Fanburg, BL
Zhang, HB
Kwiatkowski, DJ
Noonan, DJ
机构
[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
关键词
D O I
10.1074/jbc.M401912200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页码:23114 / 23122
页数:9
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