期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 22, 页码 23114-23122出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M401912200
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资金
- NHLBI NIH HHS [HL67321, KO8 HL74113-01] Funding Source: Medline
- NINDS NIH HHS [NS31535] Funding Source: Medline
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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