Reuveny Adriana, Elhanany Hadas, Volk Talila
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Mech Dev. 2009 Jan-Feb;126(1-2):30-41. doi: 10.1016/j.mod.2008.10.004. Epub 2008 Oct 17.
The selective sensitivity of cells to programmed cell death (PCD) depends on the positive and negative death-inducing signals that converge into the apoptotic pathway. In Drosophila, the midline glial (MG) cells undergo selective death during development. Here, we show that the long isoform of the RNA-binding protein Held Out Wing (HOW(L)) is essential for enhancing the sensitivity of the MG cells to PCD. In how mutant embryos, the number of MG cells was elevated. This phenotype could be rescued by midline expression of the HOW(L) repressor isoform. In how mutant embryos, the levels of the caspase inhibitor of apoptosis, Diap1 were elevated, in parallel to reduction in the levels of activated caspase. Similarly, reducing the levels of HOW in S2 cells led to elevation of Diap1, whereas over expression of HOW(L) promoted reduction of Diap1 protein as well as mRNA levels. Importantly, deletion of the two HOW binding sites from diap1 3'UTR abrogated HOW-dependent repression of Diap1, suggesting that HOW represses diap1 by binding to its 3'UTR. These results suggest that HOW(L) enhances the sensitivity of MG cells to apoptotic signals by reducing the levels of diap1 in these cells in, demonstrating a novel mode of regulation of PCD at the mRNA level.
细胞对程序性细胞死亡（PCD）的选择性敏感性取决于汇聚到凋亡途径中的正负死亡诱导信号。在果蝇中，中线神经胶质（MG）细胞在发育过程中经历选择性死亡。在这里，我们表明RNA结合蛋白伸出翅膀（HOW(L)）的长异构体对于增强MG细胞对PCD的敏感性至关重要。在how突变胚胎中，MG细胞的数量增加。这种表型可以通过HOW(L)阻遏异构体的中线表达来挽救。在how突变胚胎中，凋亡的半胱天冬酶抑制剂Diap1的水平升高，同时活化的半胱天冬酶水平降低。同样，降低S2细胞中HOW的水平会导致Diap1升高，而HOW(L)的过表达促进Diap1蛋白以及mRNA水平的降低。重要的是，从diap1 3'UTR中删除两个HOW结合位点消除了HOW对Diap1的依赖性抑制，表明HOW通过结合其3'UTR来抑制diap1。这些结果表明，HOW(L)通过降低这些细胞中diap1的水平来增强MG细胞对凋亡信号的敏感性，证明了在mRNA水平上PCD调节的一种新模式。
