Faraldo Marisa M, Deugnier Marie-Ange, Tlouzeau Sylvie, Thiery Jean Paul, Glukhova Marina A
Unité Mixte Recherche 144, Centre National de la Recherche Scientifique-Institut Curie, Section de Recherche, 75248 Paris, France.
Mol Biol Cell. 2002 Oct;13(10):3521-31. doi: 10.1091/mbc.e02-02-0086.
To study the mechanism of beta1-integrin function in vivo, we have generated transgenic mouse expressing a dominant negative mutant of beta1-integrin under the control of mouse mammary tumor virus (MMTV) promoter (MMTV-beta1-cyto). Mammary glands from MMTV-beta1-cyto transgenic females present significant growth defects during pregnancy and lactation and impaired differentiation of secretory epithelial cells at the onset of lactation. We report herein that perturbation of beta1-integrin function in involuting mammary gland induced precocious dedifferentiation of the secretory epithelium, as shown by the premature decrease in beta-casein and whey acidic protein mRNA levels, accompanied by inactivation of STAT5, a transcription factor essential for mammary gland development and up-regulation of nuclear factor-kappaB, a negative regulator of STAT5 signaling. This is the first study demonstrating in vivo that cell-extracellular matrix interactions involving beta1-integrins play an important role in the control of milk gene transcription and in the maintenance of the mammary epithelial cell differentiated state.
为了研究β1整合素在体内的功能机制，我们构建了在小鼠乳腺肿瘤病毒（MMTV）启动子控制下表达β1整合素显性负性突变体的转基因小鼠（MMTV-β1-cyto）。MMTV-β1-cyto转基因雌性小鼠的乳腺在妊娠和哺乳期出现明显的生长缺陷，并且在泌乳开始时分泌上皮细胞的分化受损。我们在此报告，在退化期乳腺中β1整合素功能的扰动诱导了分泌上皮的早熟去分化，表现为β-酪蛋白和乳清酸性蛋白mRNA水平过早下降，同时伴有STAT5失活，STAT5是乳腺发育所必需的转录因子，以及核因子-κB上调，核因子-κB是STAT5信号的负调节因子。这是第一项在体内证明涉及β1整合素的细胞-细胞外基质相互作用在控制乳汁基因转录和维持乳腺上皮细胞分化状态中起重要作用的研究。
