Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor α in MCF-7 cells
Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor α in MCF-7 cells
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DOI：
10.1074/jbc.m313191200
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发表时间：
2004-05-07
影响因子：
4.8
通讯作者：
Andó, S
中科院分区：
文献类型：
--
作者：
Catalano, S;Mauro, L;Andó, S
瘦素是一种具有多种生物作用的激素，主要由脂肪组织产生。在人类中，血浆水平与全身脂肪相关，并且肥胖女性的血浆水平较高。瘦素的功能之一是能够刺激正常细胞和肿瘤细胞的生长。我们证明瘦素可诱导 MCF-7 细胞中的芳香酶活性，证明其在增强原位雌二醇产生和促进雌激素依赖性乳腺癌进展方面的重要作用。雌激素受体α（ERα）在乳腺癌的发展中发挥重要作用，可以以不依赖配体的方式转录激活。考虑到未配体的 ERα 是丝裂原激活蛋白激酶 (MAPK) 信号的效应子，并且瘦素能够通过 Janus 激酶激活 Ras 依赖性 MAPK 通路，在本研究中，我们研究了瘦素反式激活 ERα 的能力。我们提供的证据表明瘦素能够在乳腺癌细胞系中重现 ERα 反式激活的经典特征：核定位、其 mRNA 和蛋白质水平下调以及经典雌激素依赖性基因（如 pS2）的上调。使用转染的核 ER 报告基因进行的反式激活实验表明，MCF-7 或 HeLa 细胞中的 ERα 均被激活。使用显性失活 ERK2 或 MAPK 抑制剂 PD 98059，我们发现瘦素通过 MAPK 途径激活 ERα。 N 端转录激活功能 1 似乎对于瘦素反应至关重要。最后，值得注意的是，瘦素暴露也会增强雌二醇诱导的 ERα 激活。因此，我们能够证明瘦素诱导的雌激素信号放大是通过增强原位 E-2 产生以及 ERα 的直接功能激活而发生的。
Leptin is a hormone with multiple biological actions, produced predominantly by adipose tissue. In humans, plasma levels correlate with total body fat, and high concentrations occur in obese women. Among its functions, leptin is able to stimulate normal and tumor cell growth. We demonstrated that leptin induces aromatase activity in MCF-7 cells evidencing its important role in enhancing in situ estradiol production and promoting estrogen-dependent breast cancer progression. Estrogen receptor alpha (ERalpha), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. Taking into account that unliganded ERalpha is an effector of mitogen-activated protein kinase (MAPK) signal and that leptin is able, via Janus kinase, to activate the Ras-dependent MAPK pathway, in the present study we investigate the ability of leptin to transactivate ERalpha. We provided evidence that leptin is able to reproduce the classic features of ERalpha transactivation in a breast cancer cell line: nuclear localization, down-regulation of its mRNA and protein levels, and up-regulation of a classic estrogen-dependent gene such as pS2. Transactivation experiments with a transfected reporter gene for nuclear ER showed an activation of ERalpha either in MCF-7 or in HeLa cells. Using a dominant negative ERK2 or the MAPK inhibitor PD 98059, we showed that leptin activates the ERalpha through the MAPK pathway. The N-terminal transcriptional activation function 1 appears essential for the leptin response. Finally, it is worth noting that leptin exposure potentates also the estradiol-induced activation of ERalpha. Thus, we are able to demonstrate that the amplification of estrogen signal induced by leptin occurs through an enhancing in situ E-2 production as well as a direct functional activation of ERalpha.