MEKK1 activation of human estrogen receptor alpha and stimulation of the agonistic activity of 4-hydroxytamoxifen in endometrial and ovarian cancer cells.
MEKK1 activation of human estrogen receptor alpha and stimulation of the agonistic activity of 4-hydroxytamoxifen in endometrial and ovarian cancer cells.
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DOI：
10.1210/mend.14.11.0554
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发表时间：
2000-11
影响因子：
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通讯作者：
Heehyoung Lee;Feng Jiang;Qiang Wang;S. Nicosia;Jianhua Yang;Bing Su;Wenlong Bai
中科院分区：
文献类型：
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作者：
Heehyoung Lee;Feng Jiang;Qiang Wang;S. Nicosia;Jianhua Yang;Bing Su;Wenlong Bai
雌激素是刺激女性生殖系统正常和转化上皮细胞生长的有丝分裂原。雌激素的作用是通过雌激素受体介导的，雌激素受体是配体调节的转录因子。他莫昔芬是一种选择性雌激素受体调节剂，在乳腺中是雌激素受体拮抗剂，在子宫中是激动剂。在目前的研究中，我们表明，组成型活性MEKK 1，而不是RAF或MEKK 2的共表达，显着增加了子宫内膜癌和卵巢癌细胞中受体的转录活性。野生型MEKK 1和活性Rac 1（其在MEKK 1上游起作用）的表达也增加了受体的活性，而显性阴性MEKK 1的共表达阻断了Rac 1的诱导，表明内源性MEKK 1能够激活受体。另外的实验表明，MEKK 1诱导的激活是通过Jun N-末端激酶和p38/Hog 1介导的，并且不依赖于受体上已知的磷酸化位点。p38，但不是Jun N-末端激酶，有效地磷酸化的受体在免疫复合物激酶测定，表明在受体活化的两个激酶的差异参与。更重要的是，组成型活性MEKK 1的表达将4-羟基他莫昔芬的激动活性增加到与17 β-雌二醇相当的水平，并完全阻断其拮抗活性。这些发现表明，他莫昔芬化合物的子宫特异性激动活性可能由MEKK 1下游激酶的状态决定。
Estrogens are mitogens that stimulate the growth of both normal and transformed epithelial cells of the female reproductive system. The effect of estrogens is mediated through the estrogen receptors, which are ligand-regulated transcription factors. Tamoxifen, a selective estrogen receptor modulator, functions as an estrogen receptor antagonist in breast but an agonist in uterus. In the current study, we show that coexpression of a constitutively active MEKK1, but not RAF or MEKK2, significantly increases the transcriptional activity of the receptor in endometrial and ovarian cancer cells. The expression of wild-type MEKK1 and an active Rac1, which functions upstream of MEKK1, also increased the activity of the receptor while coexpression of dominant negative MEKK1 blocked the Rac1 induction, indicating that endogenous MEKK1 is capable of activating the receptor. Additional experiments demonstrated that the MEKK1-induced activation was mediated through both Jun N-terminal kinases and p38/Hog1 and was independent of the known phosphorylation sites on the receptor. p38, but not Jun N-terminal kinases, efficiently phosphorylated the receptor in immunocomplex kinase assays, suggesting a differential involvement of the two kinases in the receptor activation. More importantly, the expression of the constitutively active MEKK1 increased the agonistic activity of 4-hydroxytamoxifen to a level comparable to that of 17beta-estradiol and fully blocked its antagonistic activity. These findings suggest that the uterine-specific agonistic activity of the tamoxifen compound may be determined by the status of kinases acting downstream of MEKK1.