Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation
Key roles for MED1 LxxLL motifs in pubertal mammary gland development and luminal-cell differentiation
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DOI：
10.1073/pnas.1001814107
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发表时间：
2010-04-13
影响因子：
11.1
通讯作者：
Zhang, Xiaoting
中科院分区：
文献类型：
--
作者：
Jiang, Pingping;Hu, Qiuping;Zhang, Xiaoting
介体是近年来出现的一种重要的转录因子，它直接将转录因子的信号转导到转录机制中。在核受体的情况下，体外研究表明，介体的转录共激活因子功能涉及MED 1亚基通过其两个经典的LxxLL基序与受体AF 2结构域的直接配体依赖性相互作用。然而，尽管有强有力的体外证据，目前几乎没有关于LxxLL基序在MED 1或其他共激活剂中的体内功能的信息。为此，我们已经产生了MED 1 LxxLL基序突变敲入小鼠。有趣的是，这些小鼠既能存活又能生育，并且没有表现出任何明显的大体异常。然而，他们确实表现出严重的缺陷，在青春期乳腺发育。与这种表型一致，以及强配体依赖性雌激素受体（ER）α-介体相互作用的丧失，许多已知的ER α调节基因的表达在MED 1突变型乳腺上皮细胞中下调，并且不再对雌激素刺激产生反应。相关的，雌激素刺激的MED 1突变小鼠乳腺导管生长也大大减少。最后，其他研究表明，MED 1在不同类型的乳腺上皮细胞中差异表达，其LxxLL基序在乳腺腔上皮细胞分化和祖细胞/干细胞确定中发挥作用。我们的研究结果建立了一个关键的核受体和细胞特异性的MED 1 LxxLL基序在体内的作用，通过中介ER α相互作用，在乳腺发育。
Mediator recently has emerged as a central player in the direct transduction of signals from transcription factors to the general transcriptional machinery. In the case of nuclear receptors, in vitro studies have shown that the transcriptional coactivator function of the Mediator involves direct ligand-dependent interactions of the MED1 subunit, through its two classical LxxLL motifs, with the receptor AF2 domain. However, despite the strong in vitro evidence, there currently is little information regarding in vivo functions of the LxxLL motifs either in MED1 or in other coactivators. Toward this end, we have generated MED1 LxxLL motif-mutant knockin mice. Interestingly, these mice are both viable and fertile and do not exhibit any apparent gross abnormalities. However, they do exhibit severe defects in pubertal mammary gland development. Consistent with this phenotype, as well as loss of the strong ligand-dependent estrogen receptor (ER)alpha-Mediator interaction, expression of a number of known ER alpha-regulated genes was down-regulated in MED1-mutant mammary epithelial cells and could no longer respond to estrogen stimulation. Related, estrogen-stimulated mammary duct growth in MED1-mutant mice was also greatly diminished. Finally, additional studies show that MED1 is differentially expressed in different types of mammary epithelial cells and that its LxxLL motifs play a role in mammary luminal epithelial cell differentiation and progenitor/stem cell determination. Our results establish a key nuclear receptor- and cell-specific in vivo role for MED1 LxxLL motifs, through Mediator-ER alpha interactions, in mammary gland development.