Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3
Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3
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DOI：
10.1101/gad.13.19.2604
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发表时间：
1999-10-01
影响因子：
10.5
通讯作者：
Watson, CJ
中科院分区：
文献类型：
--
作者：
Chapman, RS;Lourenco, PC;Watson, CJ
乳腺退化的特征是上皮细胞大量凋亡。在退化开始时，Stat 3被特异性激活。为了解决这个信号分子在乳腺上皮细胞凋亡的功能，我们已经产生了条件敲除Stat 3使用Cre-lox重组系统。断奶后，细胞凋亡减少和退化的显着延迟发生在Stat 3无效的乳腺组织。退化通常与IGFBP-5水平的显著增加相关。这在对照腺体中观察到，但在Stat 3不存在的情况下没有观察到。IGFBP-5被认为通过将IGF-1隔离到酪蛋白胶束中，从而抑制其存活功能来诱导细胞凋亡。我们的研究结果表明IGFBP-5是Stat 3的直接或间接靶点，其上调对正常退化至关重要。在Stat 3缺失的情况下，Stat 5、Bcl-x（L）或Bax的调节没有观察到显著差异。Stat 1的过早激活和p53和p21水平的增加发生，并可能作为补偿机制，最终开始在Stat 3空乳腺中观察到的退化。这是第一次证明了Stat因子在体内生理性细胞凋亡启动信号中的重要性。
Mammary gland involution is characterized by extensive apoptosis of the epithelial cells. At the onset of involution, Stat3 is specifically activated. To address the function of this signaling molecule in mammary epithelial apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox recombination system. Following weaning, a decrease in apoptosis and a dramatic delay of involution occurred in Stat3 null mammary tissue. Involution is normally associated with a significant increase in IGFBP-5 levels. This was observed in control glands, but not in the absence of Stat3. IGFBP-5 has been suggested to induce apoptosis by sequestering IGF-1 to casein micelles, thereby inhibiting its survival function. Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution. No marked differences were seen in the regulation of Stat5, Bcl-x(L), or Bax in the absence of Stat3. Precocious activation of Stat1 and increases in levels of p53 and p21 occurred and may act as compensatory mechanisms for the eventual initiation of involution observed in Stat3 null mammary glands. This is the first demonstration of the importance of a Stat factor in signaling the initiation of physiological apoptosis in vivo.