HuD, a neuronal-specific RNA-binding protein, increases the in vivo stability of MYCN RNA
HuD, a neuronal-specific RNA-binding protein, increases the in vivo stability of MYCN RNA
复制标题
DOI：
10.1074/jbc.m106966200
复制
发表时间：
2002-01-18
影响因子：
4.8
通讯作者：
Cohn, SL
中科院分区：
文献类型：
--
作者：
Manohar, CF;Short, ML;Cohn, SL
MYCN扩增和随后的表达失调在决定神经母细胞瘤的临床行为中起着至关重要的作用。MYCN的表达增强赋予神经母细胞瘤细胞生长潜力，并且MYCN表达与神经母细胞瘤发展之间的直接联系已在转基因小鼠研究中得到证实。虽然MYCN调控的分子途径尚未完全阐明，但转录后机制似乎很重要。先前，我们报道了胚胎致死异常视觉样（ELAV）蛋白以高特异性结合MYCN 3 '非翻译区内的至少两个富含AU的元件。在这项研究中，我们表征了MYCN 3 '-非翻译区内顺式作用元件使细胞中mRNA不稳定的能力，并检查了其与ELAV蛋白HuD相互作用的功能后果。我们发现MYCN X非翻译区中至少有4个顺式作用元件能够发出稳定异源mRNA降解的信号。HuD的异位过表达显著抑制由全长MYCN 3 '-非翻译区和体内含有HuD结合位点的顺式作用不稳定元件介导的RNA衰变。HuD可能通过稳定MYCN mRNA，从而提高该癌基因表达的稳态水平，从而导致神经母细胞瘤细胞的恶性表型。
MYCN amplification and consequent deregulated expression plays a crucial role in determining the clinical behavior of neuroblastoma. Enhanced expression of MYCN confers growth potential to neuroblastoma cells, and a direct link between MYCN expression and the development of neuroblastoma has been demonstrated in transgenic mice studies. Although the molecular pathways underlying the regulation of MYCN have not been fully elucidated, post-transcriptional mechanisms appear to be important. Previously, we reported that an embryonic lethal abnormal vision-like (ELAV) protein binds with high specificity to at least two AU-rich elements within the MYCN 3'-untranslated region. In this study, we characterized the ability of cis-acting elements within the MYCN 3'-untranslated region to destabilize mRNA in cells and examined the functional consequences of its interactions with the ELAV protein HuD. We show that at least 4 cis-acting elements within the MYCN X-untranslated region are able to signal the degradation of stable heterologous mRNA. Ectopic overexpression of HuD dramatically inhibits RNA decay mediated by the full-length MYCN 3'-untranslated region and cis-acting destabilizing elements that harbor HuD binding sites in vivo. HuD may contribute to the malignant phenotype of neuroblastoma cells by stabilizing MYCN mRNA, thereby enhancing steady-state levels of expression of this oncogene.