Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324 Centre for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Mol Biol Cell. 2013 Oct;24(19):3085-96. doi: 10.1091/mbc.E13-05-0239. Epub 2013 Jul 31.
The X-linked gene Rnf12 encodes the ubiquitin ligase really interesting new gene (RING) finger LIM domain-interacting protein (RLIM)/RING finger protein 12 (Rnf12), which serves as a major sex-specific epigenetic regulator of female mouse nurturing tissues. Early during embryogenesis, RLIM/Rnf12 expressed from the maternal allele is crucial for the development of extraembryonic trophoblast cells. In contrast, in mammary glands of pregnant and lactating adult females RLIM/Rnf12 expressed from the paternal allele functions as a critical survival factor for milk-producing alveolar cells. Although RLIM/Rnf12 is detected mostly in the nucleus, little is known about how and in which cellular compartment(s) RLIM/Rnf12 mediates its biological functions. Here we demonstrate that RLIM/Rnf12 protein shuttles between nucleus and cytoplasm and this is regulated by phosphorylation of serine S214 located within its nuclear localization sequence. We show that shuttling is important for RLIM to exert its biological functions, as alveolar cell survival activity is inhibited in cells expressing shuttling-deficient nuclear or cytoplasmic RLIM/Rnf12. Thus regulated nucleocytoplasmic shuttling of RLIM/Rnf12 coordinates cellular compartments during mammary alveolar cell survival.
X 连锁基因 Rnf12 编码泛素连接酶真核生物延伸因子（RING）指 LIM 结构域相互作用蛋白（RLIM）/RING 指蛋白 12（Rnf12），它作为雌性小鼠滋养组织主要的性别特异性表观遗传调节剂。在胚胎早期，来自母本等位基因的 RLIM/Rnf12 对于滋养外胚层细胞的发育至关重要。相比之下，在怀孕和哺乳期成年雌性的乳腺中，来自父本等位基因的 RLIM/Rnf12 作为产奶肺泡细胞的关键存活因子发挥作用。尽管 RLIM/Rnf12 主要在核内检测到，但对于 RLIM/Rnf12 如何以及在哪个细胞区室（s）中介导其生物学功能知之甚少。在这里，我们证明 RLIM/Rnf12 蛋白在核和细胞质之间穿梭，这是由其核定位序列中丝氨酸 S214 的磷酸化调节的。我们表明，穿梭对于 RLIM 发挥其生物学功能很重要，因为在表达穿梭缺陷的核或细胞质 RLIM/Rnf12 的细胞中，肺泡细胞存活活性受到抑制。因此，RLIM/Rnf12 的这种受调控的核质穿梭协调了乳腺肺泡细胞存活过程中的细胞区室。
