Tao Wensi, Moore Robert, Smith Elizabeth R, Xu Xiang-Xi
Sylvester Comprehensive Cancer Center, and Department of Cell Biology, Graduate Program in Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
PLoS One. 2014 Oct 31;9(10):e110737. doi: 10.1371/journal.pone.0110737. eCollection 2014.
Disabled-2 (Dab2) is a widely expressed endocytic adaptor that was first isolated as a 96 KDa phospho-protein, p96, involved in MAPK signal transduction. Dab2 expression is lost in several cancer types including breast cancer, and Dab2 is thought to have a tumor suppressor function. In mammary epithelia, Dab2 was induced upon pregnancy and further elevated during lactation. We constructed mutant mice with a mosaic Dab2 gene deletion to bypass early embryonic lethality and to investigate the roles of Dab2 in mammary physiology. Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution. In primary cultures of mouse mammary epithelial cells, Dab2 proteins were also induced by estrogen, progesterone, and/or prolactin. Dab2 null mammary epithelial cells were refractory to growth suppression induced by TGF-beta. However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells. We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.
Disabled-2（Dab2）是一种广泛表达的内吞衔接蛋白，最初作为一种参与丝裂原活化蛋白激酶（MAPK）信号转导的96千道尔顿磷蛋白p96被分离出来。Dab2在包括乳腺癌在内的多种癌症类型中表达缺失，并且被认为具有肿瘤抑制功能。在乳腺上皮细胞中，Dab2在怀孕时被诱导表达，并在哺乳期进一步升高。我们构建了具有镶嵌式Dab2基因缺失的突变小鼠，以绕过早期胚胎致死性，并研究Dab2在乳腺生理学中的作用。Dab2的缺失对泌乳有细微影响，但Dab2缺陷型乳腺在退化过程中显示出细胞清除明显延迟。在小鼠乳腺上皮细胞的原代培养中，雌激素、孕酮和/或催乳素也可诱导Dab2蛋白表达。Dab2基因敲除的乳腺上皮细胞对转化生长因子-β（TGF-β）诱导的生长抑制具有抗性。然而，Dab2的缺失并不影响Smad2的磷酸化；相反，在Dab2缺陷型细胞中，TGF-β刺激的MAPK激活增强。我们得出结论，激素可诱导Dab2表达，并且Dab2在调节TGF-β信号传导中发挥作用，以增强退化过程中乳腺上皮细胞的凋亡清除。
