Long noncoding RNA Saf and splicing factor 45 increase soluble Fas and resistance to apoptosis.
Long noncoding RNA Saf and splicing factor 45 increase soluble Fas and resistance to apoptosis.
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DOI：
10.18632/oncotarget.7329
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发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Wilber A
中科院分区：
文献类型：
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作者：
Villamizar O;Chambers CB;Riberdy JM;Persons DA;Wilber A
在多细胞生物体中，细胞生长和分化部分由程序性细胞死亡或凋亡控制。一个主要的凋亡途径是由Fas受体（Fas）-Fas配体（FasL）相互作用触发的。肿瘤细胞通常对Fas介导的凋亡具有抗性，通过下调Fas逃避Fas信号，并产生结合FasL的可溶性Fas蛋白，从而阻断凋亡。可溶性Fas（sFas）是Fas前体mRNA的选择性剪接产物，通常通过排除外显子6（FasΔ Ex 6）内编码的跨膜序列而产生。长链非编码RNA（lncRNA）与其他RNA、DNA和蛋白质相互作用以调节基因表达。一种lncRNA，Fas反义或Saf，被证明通过未知的机制参与Fas前体mRNA的选择性剪接。我们发现，Saf位于细胞核中，在那里它与Fas受体前体mRNA和人剪接因子45（SPF 45）相互作用，以促进选择性剪接和排除外显子6。该产物是一种可溶性Fas蛋白，可保护细胞免受FasL诱导的凋亡。总的来说，这些研究揭示了一种新的机制，通过lncRNA及其蛋白质伴侣来调节这种关键的细胞死亡程序。
In multicellular organisms, cell growth and differentiation is controlled in part by programmed cell death or apoptosis. One major apoptotic pathway is triggered by Fas receptor (Fas)-Fas ligand (FasL) interaction. Neoplastic cells are frequently resistant to Fas-mediated apoptosis, evade Fas signals through down regulation of Fas and produce soluble Fas proteins that bind FasL thereby blocking apoptosis. Soluble Fas (sFas) is an alternative splice product of Fas pre-mRNA, commonly created by exclusion of transmembrane spanning sequences encoded within exon 6 (FasΔEx6). Long non-coding RNAs (lncRNAs) interact with other RNAs, DNA, and proteins to regulate gene expression. One lncRNA, Fas-antisense or Saf, was shown to participate in alternative splicing of Fas pre-mRNA through unknown mechanisms. We show that Saf is localized in the nucleus where it interacts with Fas receptor pre-mRNA and human splicing factor 45 (SPF45) to facilitate alternative splicing and exclusion of exon 6. The product is a soluble Fas protein that protects cells against FasL-induced apoptosis. Collectively, these studies reveal a novel mechanism to modulate this critical cell death program by an lncRNA and its protein partner.