SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice.
SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice.
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DOI：
10.1186/bcr1632
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Gu Y
中科院分区：
文献类型：
--
作者：
Li H;Rajendran GK;Liu N;Ware C;Rubin BP;Gu Y
雌激素和胰岛素样生长因子-1（IGF-1）在乳腺发育和乳腺癌中起重要作用。SirT 1是一种高度保守的蛋白质脱乙酰酶，在低等生物中可以调节胰岛素/IGF-1信号传导，在哺乳动物细胞中也可以调节越来越多的转录因子，包括NF-κB。然而，SirT 1是否调节乳腺发育和功能的IGF-1信号转导尚不清楚。在本研究中，通过研究SirT 1缺陷小鼠来研究SirT 1的这种作用。SirT 1缺陷型（SirT 1 ko/ko）小鼠是通过将SirT 1基因（SirT 1co/co）中携带条件性靶向突变的新品系小鼠与CMV-Cre转基因小鼠杂交产生的。整体安装和组织学分析，免疫荧光染色，免疫组织化学和蛋白质印迹法用于表征处女和妊娠小鼠乳腺发育。外源性雌激素的作用也通过在肩胛下区域皮下植入缓释颗粒来检查。雄性和雌性SirT 1 ko/ko小鼠都可以生育，尽管生长迟缓表型。处女SirT 1 ko/ko小鼠表现出阻碍导管形态发生，而怀孕的SirT 1 ko/ko小鼠表现出泌乳失败，由于不发达的小叶肺泡网络。雌激素植入足以挽救导管形态发生。外源性雌激素逆转了SirT 1 ko/ko乳腺组织中IGF-1结合蛋白-1表达的基础水平升高，但不逆转IκBα表达的基础水平升高，表明雌激素水平升高可促进局部IGF-1的产生并挽救导管形态发生。此外，TNFα处理增强了SirT 1 ko/ko细胞中新合成的IκBα的水平。因此，SirT 1缺陷会影响细胞对多种外在信号的反应。SirT 1调节IGF-1信号传导，对小鼠的生长调节和乳腺发育至关重要。SirT 1缺陷使IGF-1结合蛋白-1的表达失调，并减弱IGF-1信号的作用，包括雌激素刺激的局部IGF-1信号传导对导管形态发生的影响。这些结果表明，SirT 1的酶活性可能会影响乳腺上皮细胞的正常生长和恶性生长。
Estrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-κB, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice. SirT1-deficient (SirT1ko/ko) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1co/co) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region. Both male and female SirT1ko/ko mice can be fertile despite the growth retardation phenotype. Virgin SirT1ko/ko mice displayed impeded ductal morphogenesis, whereas pregnant SirT1ko/ko mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1ko/ko mammary tissues, but not that of IκBα expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFα treatment enhanced the level of the newly synthesized IκBα in SirT1ko/ko cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals. SirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells.