PTEN overexpression suppresses proliferation and differentiation and enhances apoptosis of the mouse mammary epithelium
PTEN overexpression suppresses proliferation and differentiation and enhances apoptosis of the mouse mammary epithelium
复制标题
DOI：
10.1172/jci0213829
复制
发表时间：
2002-09-01
影响因子：
15.9
通讯作者：
LeRoith, D
中科院分区：
文献类型：
--
作者：
Dupont, J;Renou, JP;LeRoith, D
磷酸酶PTEN调节生长、粘附和凋亡以及许多其他细胞过程。为了研究其在小鼠乳腺发育过程中的作用，我们产生了MK-PTEN，一种转基因小鼠模型，其中人PTEN在青春期、妊娠、哺乳和退化期间在导管和肺泡乳腺上皮中过表达。青春期未孕小鼠乳腺组织中未观察到明显表型。然而，MK-PTEN雌性小鼠不能正常分泌乳汁，大约30%的幼崽死亡，幸存者表现出生长迟缓。相反，由野生型养母喂养的转基因后代发育正常。这种表型与由于细胞增殖减少和凋亡增加而导致的肺泡上皮细胞数量减少一致。使用乳腺富集的cDNA微阵列，我们确定了几个基因，优先在MK-PTEN乳腺组织中表达，包括IGF结合蛋白5（Igfbp 5）基因，和其他的表达减少，包括c-Jun氨基末端激酶的基因。分泌上皮细胞分化受损，作为衡量的特定乳蛋白基因的表达。MK-PTEN小鼠也表现出Akt磷酸化状态降低50%。总之，这些结果表明，PTEN控制乳腺发育，因此，泌乳。
The phosphatase PTEN regulates growth, adhesion, and apoptosis, among many other cell processes. To investigate its role during mouse mammary gland development, we generated MK-PTEN, a transgenic mouse model in which human PTEN is overexpressed in ductal and alveolar mammary epithelium during puberty, pregnancy, lactation, and involution. No obvious phenotype was observed in mammary tissue of pubescent virgin mice. However, MK-PTEN females could not lactate normally, and similar to30% of pups died, with survivors exhibiting growth retardation. Transgenic offspring nursed by wild-type foster mothers, conversely, developed normally. This phenotype is consistent with a reduced number of alveolar epithelial cells due to a decrease in cell proliferation and an increase in apoptosis. Using mammary-enriched cDNA microarrays, we identified several genes that were preferentially expressed in MK-PTEN mammary tissue, including the IGF-binding protein-5 (Igfbp5) gene, and others whose expression was reduced, including the genes for c-Jun amino-terminal kinase. Secretory epithelial cell differentiation was impaired, as measured by the expression of specific milk protein genes. MK-PTEN mice also exhibited a 50% decrease in the phosphorylation state of Akt. Taken together, these results suggest that PTEN controls mammary gland development and, consequently, lactation.