Loss of p19ARF enhances the defects of Mdm2 overexpression in the mammary gland
Loss of p19ARF enhances the defects of Mdm2 overexpression in the mammary gland
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DOI：
10.1038/sj.onc.1205441
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发表时间：
2002-05-16
期刊：
影响因子：
8
通讯作者：
Lozano, G
中科院分区：
文献类型：
--
作者：
Foster, CJ;Lozano, G
由鼠双微体2（Mdm 2）基因编码的蛋白质使肿瘤抑制因子p53的功能失活。mdm 2转基因（BLGmdm 2）在乳腺上皮的靶向表达破坏了细胞周期，导致多轮DNA合成而没有适当的细胞分裂，从而导致乳腺发育不良。转基因小鼠乳腺上皮中的这些表型不依赖于p53或转录因子E2 F1，因为携带BLGmdm 2转基因的这些基因缺失的小鼠表现出与仅携带BLGmdm 2转基因的小鼠相似的缺陷。p19 ARF是INK 4a/ARF基因座的选择性剪接产物，已显示与MDM 2直接相互作用。因此，BLGmdm 2转基因小鼠p19 ARF无效，以获得洞察mdm 2过表达破坏细胞周期的机制。在没有p19 ARF的情况下，BLGmdm 2表型比BLGmdm 2小鼠更差，并且早在妊娠第15天就可见。到泌乳第5天，表型非常明显。乳腺的组织学分析显示导管分支减少，小叶肺泡结构变小和变少，管腔分泌物减少。由于在没有胞质分裂的情况下持续复制，存在多核和增大的细胞。因此，在该体内系统中p19 ARF的缺乏增强了mdm 2过表达引起的缺陷。
The protein encoded by the murine double minute 2 (Mdm2) gene inactivates the function of the tumor suppressor p53. The targeted expression of the mdm2 transgene (BLGmdm2) to the mammary epithelium disrupts the cell cycle, causing multiple rounds of DNA synthesis without proper cell division and consequently poor mammary gland development. These phenotypes in the mammary epithelia of the transgenic mice are not dependent on either p53 or the transcription factor E2F1, as mice null for these genes carrying the BLGmdm2 transgene exhibit similar defects to mice carrying the BLGmdm2 transgene alone. p19ARF, an alternative splice product of the INK4a/ARF locus, has been shown to interact directly with MDM2. Therefore, BLGmdm2 transgenic mice null for p19ARF were created to gain insight into the mechanism by which mdm2 overexpression disrupts the cell cycle. The BLGmdm2 phenotype in the absence of p19ARF was worse than BLGmdm2 mice and visible as early as day 15 of pregnancy. By day 5 of lactation the phenotype was very pronounced. Histological analysis of the mammary gland showed a decrease in ductal branching, smaller and fewer lobuloalveolar structures, and a decrease in luminal secretions. Multinucleated and enlarged cells were present due to continued replication in the absence of cytokinesis. Thus, the absence of p19ARF in this in vivo system enhanced the defect caused by mdm2 overexpression.