PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells
PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells
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DOI：
10.3892/ijo.2011.956
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发表时间：
2011-05-01
影响因子：
5.2
通讯作者：
Taylor-Papadimitriou, Joyce
中科院分区：
文献类型：
--
作者：
Catchpole, Steven;Spencer-Dene, Bradley;Taylor-Papadimitriou, Joyce
JARID 1/KDM 5蛋白质家族的四个成员是更大的ARID（富含AT的DNA结合结构域）家族的一个亚组，已显示使组蛋白3（H3 K4 me 3）上的三甲基化赖氨酸4去甲基化，组蛋白3是与活跃转录基因相关的染色质标记。在一些低等生物中发现了JARID 1的单一同源物，并且在小鼠和人类中发现的四种蛋白质的功能可能是特异性的或重叠的。为了研究JARID 1B蛋白的功能，我们检测了小鼠中基因缺失的影响。系统性敲除Jarid 1b导致早期胚胎死亡，而不表达相关Jarid 1A基因的小鼠是可行的和可育的。第二种小鼠品系表达的Jarid 1b基因与ARID结构域删除是可行的和肥沃的，但显示乳腺表型，其中终端芽发育和侧支延迟在青春期和妊娠早期。由于末端芽的发育完全依赖于雌激素受体（ER α）的信号传导，我们研究了Delta ARID小鼠中靶基因（孕酮受体）的表达，发现水平与野生型相比有所降低。JARID 1B在ER+乳腺癌和乳腺癌细胞系中广泛表达，并且通过用标记的ER a和JARID 1B基因转染的细胞中的免疫共沉淀来证明与ER a的相互作用。在MCF-7细胞中使用shRNAi下调JARID 1B的表达导致E2刺激的裸鼠肿瘤生长显著减少。这些数据证明了Jarid 1B在早期胚胎发育、正常乳腺的发育和分化以及雌激素诱导的ER+乳腺癌生长中的特定作用。
The four members of the JARID1/KDM5 family of proteins, a sub-group of the larger ARID (AT rich DNA binding domain) family, have been shown to demethylate trimethylated lysine 4 on histone 3 (H3K4me3), a chromatin mark associated with actively transcribed genes. In some lower organisms a single homologue of JARID1 is found, and functions of the four proteins found in mice and humans may be specific or overlapping. To investigate the function of the JARID1B protein we examined the effects of deletion of the gene in mice. Systemic knock out of Jarid1b resulted in early embryonic lethality, whereas mice not expressing the related Jarid1A gene are viable and fertile. A second mouse strain expressing a Jarid1b gene with the ARID domain deleted was viable and fertile but displayed a mammary phenotype, where terminal end bud development and side branching was delayed at puberty and in early pregnancy. Since development of terminal end buds are completely dependent on signalling from the estrogen receptor (ER alpha), we investigated the expression of a target gene (progesterone receptor) in the Delta ARID mouse and found levels to be reduced as compared to wild-type. JARID1B is widely expressed in ER+ breast cancers and breast cancer cell lines, and interaction with ERa was demonstrated by co-immunoprecipitations in cells transfected with tagged ERa and JARID1B genes. Down-regulation of expression of JARID1B using shRNAi in MCF-7 cells resulted in a dramatic decrease in E2 stimulated tumour growth in nude mice. The data demonstrate a specific role for Jarid1B in early embryonic development, in the development and differentiation of the normal mammary gland, and in estrogen induced growth of ER+ breast cancer.