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Selective degradation of excess Ldb1 by Rnf12/RLIM confers proper Ldb1 expression levels and Xlim-1/Ldb1 stoichiometry in Xenopus organizer functions.

机译:Rnf12 / RLIM对过量Ldb1的选择性降解赋予Xenopus组织者功能适当的Ldb1表达水平和Xlim-1 / Ldb1化学计量。

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摘要

The Xenopus LIM homeodomain (LIM-HD) protein, Xlim-1, is expressed in the Spemann organizer and cooperates with its positive regulator, Ldb1, to activate organizer gene expression. While this activation is presumably mediated through Xlim-1/Ldb1 tetramer formation, the mechanisms regulating proper Xlim-1/Ldb1 stoichiometry remains largely unknown. We isolated the Xenopus ortholog (XRnf12) of the RING finger protein Rnf12/RLIM and explored its functional interactions with Xlim-1 and Ldb1. Although XRnf12 functions as a E3 ubiquitin ligase for Ldb1 and causes proteasome-dependent degradation of Ldb1, we found that co-expression of a high level of Xlim-1 suppresses Ldb1 degradation by XRnf12. This suppression requires both the LIM domains of Xlim-1 and the LIM interaction domain of Ldb1, suggesting that Ldb1, when bound to Xlim-1, escapes degradation by XRnf12. We further show that a high level of Ldb1 suppresses the organizer activity of Xlim-1/Ldb1, suggesting that excess Ldb1 molecules disturb Xlim-1/Ldb1 stoichiometry. Consistent with this, Ldb1 overexpression in the dorsal marginal zone suppresses expression of several organizer genes including postulated Xlim-1 targets, and importantly, this suppression is rescued by co-expression of XRnf12. These data suggest that XRnf12 confers proper Ldb1 protein levels and Xlim-1/Ldb1 stoichiometry for their functions in the organizer. Together with the similarity in the expression pattern of Ldb1 and XRnf12 throughout early embryogenesis, we propose Rnf12/RLIM as a specific regulator of Ldb1 to ensure its proper interactions with LIM-HD proteins and possibly other Ldb1-interacting proteins in the organizer as well as in other tissues.
机译:非洲爪蟾的LIM同源域(LIM-HD)蛋白Xlim-1在Spemann组织器中表达,并与其正调控子Ldb1协同激活组织器基因表达。虽然这种激活可能是通过Xlim-1 / Ldb1四聚体的形成介导的,但调节Xlim-1 / Ldb1化学计量的合适机理仍然未知。我们分离了RING指蛋白Rnf12 / RLIM的非洲爪蟾直系同源物(XRnf12),并探索了其与Xlim-1和Ldb1的功能相互作用。尽管XRnf12充当Ldb1的E3泛素连接酶并引起Ldb1蛋白酶体依赖性降解,但我们发现高水平Xlim-1的共表达抑制XRnf12降解Ldb1。这种抑制需要Xlim-1的LIM域和Ldb1的LIM相互作用域,这表明Ldb1当绑定到Xlim-1时,可以避免XRnf12的降解。我们进一步表明,高水平的Ldb1抑制Xlim-1 / Ldb1的组织者活动,表明过量的Ldb1分子干扰Xlim-1 / Ldb1的化学计量。与此相一致,背侧边缘区的Ldb1过表达抑制了包括假定的Xlim-1靶标在内的多个组织基因的表达,重要的是,这种抑制通过XRnf12的共表达得以挽救。这些数据表明,XRnf12在组织者中具有适当的Ldb1蛋白水平和Xlim-1 / Ldb1化学计量。结合整个早期胚胎发生过程中Ldb1和XRnf12的表达模式的相似性,我们提出Rnf12 / RLIM作为Ldb1的特异性调节剂,以确保其与LIM-HD蛋白以及可能与组织器中其他与Ldb1相互作用的蛋白正确相互作用。在其他组织中。

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