Distinct roles of the three Akt isoforms in lactogenic differentiation and involution.
Distinct roles of the three Akt isoforms in lactogenic differentiation and involution.
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DOI：
10.1002/jcp.21518
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发表时间：
2008-11
影响因子：
5.6
通讯作者：
Tsichlis, Philip N.
中科院分区：
文献类型：
--
作者：
Maroulakou, Ioanna G.;Oemler, William;Naber, Stephen P.;Klebba, Ina;Kuperwasser, Charlotte;Tsichlis, Philip N.
在乳腺上皮中，三种Akt亚型在转导Neu和PyMT癌基因引发的致癌信号的能力上存在差异。因此，Akt1的消融抑制和Akt2的消融加速了两种癌基因的乳腺肿瘤发展，而Akt3的消融在表型上几乎是中性的。由于人类乳腺癌发展的风险与多次晚期妊娠相关，我们开展了一项研究，以确定在妊娠、哺乳期和哺乳期后复归期间，个体Akt亚型是否在转导激素和生长因子信号的能力上也存在差异。结果显示，Akt1的消融延缓了妊娠和哺乳期乳腺上皮细胞的分化，而Akt2的消融则起到相反的作用。最后，Akt3的消融导致了轻微的缺陷，但其表型更接近野生型小鼠。Akt1消融的表型是细胞自主的，而Akt2则不是。Akt1的消融促进细胞凋亡并加速老化，而Akt2的消融抑制细胞凋亡并延迟老化。怀孕期间的乳腺分化取决于Stat5a的磷酸化，这是由催乳素诱导的，催乳素是一种通过Akt传导信号的激素。我们发现，在妊娠晚期和哺乳期，Akt1的消融而不是Akt2或Akt3的消融会干扰Stat5a的磷酸化。我们得出结论，Akt的三种亚型在妊娠期乳腺分化中有不同的作用，这可能反映了激素信号的差异。
The three Akt isoforms differ in their ability to transduce oncogenic signals initiated by the Neu and PyMT oncogenes in mammary epithelia. As a result, ablation of Akt1 inhibits and ablation of Akt2 accelerates mammary tumor development by both oncogenes, while ablation of Akt3 is phenotypically almost neutral. Since the risk of breast cancer development in humans correlates with multiple late pregnancies, we embarked on a study to determine whether individual Akt isoforms also differ in their ability to transduce hormonal and growth factor signals during pregnancy, lactation and post-lactation involution. The results showed that the ablation of Akt1 delays the differentiation of the mammary epithelia during pregnancy and lactation, and that the ablation of Akt2 has the opposite effect. Finally, ablation of Akt3 results in minor defects, but its phenotype is closer to that of the wild type mice. Whereas the phenotype of the Akt1 ablation is cell autonomous, that of Akt2 is not. The ablation of Akt1 promotes apoptosis and accelerates involution, whereas the ablation of Akt2 inhibits apoptosis and delays involution. Mammary gland differentiation during pregnancy depends on the phosphorylation of Stat5a, which is induced by prolactin, a hormone that generates signals transduced via Akt. Here we show that the ablation of Akt1, but not the ablation of Akt2 or Akt3 interferes with the phosphorylation of Stat5a during late pregnancy and lactation. We conclude that the three Akt isoforms have different roles in mammary gland differentiation during pregnancy and this may reflect differences in hormonal signaling.
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