The Galphai and Galphaq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation.
The Galphai and Galphaq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation.
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Galphai 和 Galphaq 蛋白介导褪黑激素对类固醇/甲状腺激素受体转录活性和乳腺癌细胞增殖的影响。
DOI：
10.1111/j.1600-079x.2008.00620.x
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发表时间：
2008
影响因子：
10.3
通讯作者：
Hill,StevenM
中科院分区：
文献类型：
--
作者：
Lai,Ling;Yuan,Lin;Chen,Qi;Dong,Chunmin;Mao,Lulu;Rowan,Brian;Frasch,Tripp;Hill,StevenM
褪黑激素通过其MT 1受体而不是MT 2受体，可以调节MCF-7、T47 D和ZR-75 - 1人乳腺癌细胞系中各种核受体-雌激素受体α（ERα）和视黄酸受体α（RARα）的转录活性，但不能调节ERβ的转录活性。褪黑激素的抗增殖和核受体调节作用通过人乳腺癌细胞中表达的MT 1 G蛋白偶联受体介导。 然而，具体的G蛋白和相关的通路参与的核受体的转录调控褪黑激素还不清楚。在激活后，MT 1受体特异性地与Gαi2、Gαi3、Gαq和Gα II蛋白偶联，并且通过Gα i2蛋白的激活，褪黑激素抑制毛喉素诱导的3′，5 ′-环磷酸腺苷的产生，而褪黑激素对Gαq的激活能够抑制MCF-7乳腺癌细胞中磷脂水解和ATP诱导的三磷酸肌醇的产生。利用这些G蛋白的显性负性和显性正性形式，我们证明Gα i2蛋白介导褪黑素对雌激素诱导的ERα转录活性的抑制，而Gq蛋白介导褪黑素对类维生素A诱导的RARα转录活性的增强。然而，褪黑素的生长抑制作用是通过Gα i2和Gα q蛋白介导的。
Melatonin, via its MT1 receptor, but not the MT2 receptor, can modulate the transcriptional activity of various nuclear receptors – estrogen receptor alpha (ERα) and retinoic acid receptor alpha (RARα), but not ERβ– in MCF‐7, T47D, and ZR‐75‐1 human breast cancer cell lines. The anti‐proliferative and nuclear receptor modulatory actions of melatonin are mediated via the MT1 G protein‐coupled receptor expressed in human breast cancer cells. However, the specific G proteins and associated pathways involved in the nuclear receptor transcriptional regulation by melatonin are not yet clear. Upon activation, the MT1 receptor specifically couples to the Gαi2, Gαi3, Gαq, and Gαllproteins, and via activation of Gαi2proteins, melatonin suppresses forskolin‐induced 3′,5′‐cyclic adenosine monophosphate production, while melatonin activation of Gαq, is able to inhibit phospholipid hydrolysis and ATP’s induction of inositol triphosphate production in MCF‐7 breast cancer cells. Employing dominant‐negative and dominant‐positive) forms of these G proteins, we demonstrate that Gαi2proteins mediate the suppression of estrogen‐induced ERα transcriptional activity by melatonin, while the Gqprotein mediates the enhancement of retinoid‐induced RARα transcriptional activity by melatonin. However, the growth‐inhibitory actions of melatonin are mediated via both Gαi2and Gαqproteins.