Th-POK regulates mammary gland lactation through mTOR-SREBP pathway.
Th-POK regulates mammary gland lactation through mTOR-SREBP pathway.
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Th-POK 通过 mTOR-SREBP 途径调节乳腺泌乳。
DOI：
10.1371/journal.pgen.1007211
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发表时间：
2018-03
期刊：
影响因子：
4.5
通讯作者：
Ge G
中科院分区：
文献类型：
--
作者：
Zhang R;Ma H;Gao Y;Wu Y;Qiao Y;Geng A;Cai C;Han Y;Zeng YA;Liu X;Ge G
Th诱导的POK（Th-POK，也称为ZBTB 7 B或cKrox）转录因子是未成熟T细胞前体的谱系定型的关键调节因子。Th-POK除了辅助性T细胞分化外，其生理功能尚不清楚。在这里，我们表明，Th-POK是限制性表达的管腔上皮细胞在乳腺中，是在怀孕后期和哺乳期上调。谱系限制性表达的Th-POK在乳腺上皮细胞和T细胞中以组织特异性方式发挥不同的生物学功能。乳腺上皮细胞命运的确定不需要Th-POK。在Th-POK缺陷小鼠中，青春期的乳腺形态发生和妊娠期的肺泡发生在表型上是正常的。然而，Th-POK缺陷型小鼠在分娩后触发泌乳的开始方面存在缺陷，大细胞脂滴保留在肺泡上皮细胞内。因此，Th-POK基因敲除小鼠不能有效地分泌乳脂质和哺育后代。这种缺陷主要是由于乳腺上皮细胞的功能障碍，而不是组织微环境在Th-POK缺陷小鼠。Th-POK直接调节胰岛素受体底物-1（IRS-1）的表达和胰岛素诱导的Akt-mTOR-SREBP信号转导。Th-POK缺陷损害泌乳乳腺中IRS-1表达和Akt-mTOR-SREBP信号传导。相反，胰岛素诱导Th-POK表达。因此，Th-POK在乳腺泌乳中作为胰岛素信号传导的重要前馈调节剂发挥作用。Th-POK，也称为cKrox或ZBTB 7 B，是一种锌指转录因子，其指定未成熟T细胞前体朝向CD 4谱系的细胞命运。目前还不清楚Th-POK是否参与其他生物过程的调节。也不知道Th-POK的功能是否超出细胞命运决定。在本研究中，我们发现Th-POK在乳腺腔上皮细胞中表达，而在基底上皮细胞中不表达。尽管Th-POK在乳腺中的表达受到谱系限制，但它与乳腺上皮细胞谱系特化和乳腺发育有关。相反，Th-POK通过乳腺上皮细胞自主机制调节泌乳和乳脂质产生的开始，表明Th-POK以组织特异性方式发挥独特的功能。Th-POK调节哺乳期乳腺肺泡细胞胰岛素受体sunstrate-1的表达及胰岛素诱导的mTOR-SREBP通路激活和脂质生物合成因此，除了其在T细胞发育中充分记录的细胞命运指定功能之外，Th-POK还在泌乳乳腺中充当重要的代谢调节剂。
The Th-inducing POK (Th-POK, also known as ZBTB7B or cKrox) transcription factor is a key regulator of lineage commitment of immature T cell precursors. It is yet unclear the physiological functions of Th-POK besides helper T cell differentiation. Here we show that Th-POK is restrictedly expressed in the luminal epithelial cells in the mammary glands that is upregulated at late pregnancy and lactation. Lineage restrictedly expressed Th-POK exerts distinct biological functions in the mammary epithelial cells and T cells in a tissue-specific manner. Th-POK is not required for mammary epithelial cell fate determination. Mammary gland morphogenesis in puberty and alveologenesis in pregnancy are phenotypically normal in the Th-POK-deficient mice. However, Th-POK-deficient mice are defective in triggering the onset of lactation upon parturition with large cellular lipid droplets retained within alveolar epithelial cells. As a result, Th-POK knockout mice are unable to efficiently secret milk lipid and to nurse the offspring. Such defect is mainly attributed to the malfunctioned mammary epithelial cells, but not the tissue microenvironment in the Th-POK deficient mice. Th-POK directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling. Th-POK deficiency compromises IRS-1 expression and Akt-mTOR-SREBP signaling in the lactating mammary glands. Conversely, insulin induces Th-POK expression. Thus, Th-POK functions as an important feed-forward regulator of insulin signaling in mammary gland lactation. Th-POK, aka cKrox or ZBTB7B, is a zinc finger transcription factor that specifies the cell fate of immature T cell precursors towards the CD4 lineage. It is yet largely unknown if Th-POK participates in the regulation of other biological processes. It is also not known if Th-POK functions beyond cell fate determination. In this study, we found that Th-POK is expressed in the luminal, but not the basal epithelial cells in the mammary glands. Despite the lineage restricted expression in the mammary glands, Th-POK is dispensable for mammary epithelial cell lineage specification and mammary gland development. Rather, Th-POK regulates the onset of lactation and milk lipid production via mammary epithelial cell autonomous mechanisms, suggesting that Th-POK exerts distinct functions in a tissue specific manner. Th-POK regulates the expression of insulin receptor sunstrate-1 and insulin-induced mTOR-SREBP pathway activation and lipid biosynthesis in the mammary alveolar cells at lactation. Thus, Th-POK functions as an important metabolic regulator in the lactating mammary glands, in addition to its well documented cell fate specification functions in T cell development.
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影响因子：
7.2
作者：
Coussens, Lisa M.;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
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通讯作者：
Goldstein, Joseph L.
影响因子：
6.5
作者：
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影响因子：
64.8
作者：
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通讯作者：
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