Akt is required for Stat5 activation and mammary differentiation.
Akt is required for Stat5 activation and mammary differentiation.
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STAT5激活和乳腺分化需要AKT。
DOI：
10.1186/bcr2640
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Chodosh LA
中科院分区：
文献类型：
--
作者：
Chen CC;Boxer RB;Stairs DB;Portocarrero CP;Horton RH;Alvarez JV;Birnbaum MJ;Chodosh LA
Akt通路在调节细胞生存、增殖和代谢中起着核心作用，是人类肿瘤中最常见的激活通路之一。然而，Akt在上皮分化中的作用尚未确定。我们之前曾报道，缺乏Akt1而不是Akt2的小鼠在妊娠晚期和哺乳期表现出明显的代谢缺陷，这是由于未能上调Glut1和几种脂质合成酶。然而，尽管存在这种代谢缺陷，Akt1基因缺陷和Akt2基因缺陷的小鼠都表现出正常的乳腺上皮分化和Stat5激活。鉴于Akt家族成员的重叠功能，我们认为Akt可能在调节乳腺上皮发育中发挥重要作用，这在Akt1基因缺陷小鼠中并不明显，这是由于其他Akt亚型的补偿。为了解决这种可能性，我们杂交了携带Akt1和Akt2基因定向缺失的小鼠，并确定了在怀孕和哺乳期间对乳房分化的影响。在Akt1基因缺陷小鼠中，Akt2的一个等位基因的缺失导致了妊娠晚期Stat5激活的严重缺陷，并伴随着乳末上皮细胞分化的全面失败，表现为牛奶的三个主要成分：乳糖、脂肪和乳蛋白的产生几乎完全丧失。这一缺陷部分是由于怀孕的Akt1-/-；Akt2+/-小鼠未能上调Prlr-Jak-Stat5信号的正调控因子Id2，或下调Prlr-Jak-Stat5信号的负调控因子、小窝蛋白-1和SOC2。我们的发现表明，在Prlr-Jak-Stat5信号中对Akt的需求出乎意料，并将Akt确立为乳腺上皮分化和哺乳的重要中枢调节因子。
The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1-/-;Akt2+/- mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.
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影响因子：
7.8
作者：
Miyoshi, K;Shillingford, J M;Smith, G H;Grimm, S L;Wagner, K U;Oka, T;Rosen, J M;Robinson, G W;Hennighausen, L
通讯作者：
Hennighausen, L
影响因子：
20.3
作者：
Hoelbl A;Kovacic B;Kerenyi MA;Simma O;Warsch W;Cui Y;Beug H;Hennighausen L;Moriggl R;Sexl V
通讯作者：
Sexl V
影响因子：
--
作者：
Harris, J;Stanford, PM;Ormandy, CJ
通讯作者：
Ormandy, CJ
影响因子：
10.5
作者：
Ormandy, CJ;Camus, A;Kelly, PA
通讯作者：
Kelly, PA
影响因子：
5.6
作者：
Maroulakou, Ioanna G.;Oemler, William;Naber, Stephen P.;Klebba, Ina;Kuperwasser, Charlotte;Tsichlis, Philip N.
通讯作者：
Tsichlis, Philip N.