Regulation of the cardiomyocyte transcriptome vs translatome by endothelin-1 and insulin: translational regulation of 5′ terminal oligopyrimidine tract (TOP) mRNAs by insulin
Regulation of the cardiomyocyte transcriptome vs translatome by endothelin-1 and insulin: translational regulation of 5′ terminal oligopyrimidine tract (TOP) mRNAs by insulin
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DOI：
10.1186/1471-2164-11-343
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发表时间：
2010-05-29
期刊：
影响因子：
4.4
通讯作者：
Clerk, Angela
中科院分区：
文献类型：
--
作者：
Markou, Thomais;Marshall, Andrew K.;Clerk, Angela
背景：细胞表型的变化是由mRNA转录和翻译的潜在变化引起的。内皮素-1刺激心肌细胞肥大，伴随mRNA/蛋白质表达的相关变化和蛋白质合成速率的增加。胰岛素也会增加翻译速率，但不会促进明显的心肌细胞肥大。翻译调节的一种机制是通过5 '末端寡嘧啶束（TOP），其响应于生长刺激，促进mRNA募集到多核糖体以增加翻译。TOP mRNA包括那些编码核糖体蛋白的mRNA，但完整的mRNA还有待建立。在这里，我们使用微阵列来比较内皮素-1和胰岛素对新生大鼠心肌细胞的整体转录组的影响，以及对mRNA募集到多核糖体（即translatome）的影响。结果：在整体上，内皮素-1和胰岛素（1小时）分别促进了341和38个RNA表达的> 1.5倍显著性变化（错误发现率< 0.05）。对于这些具有这种变化水平的转录物，几乎没有翻译调节的证据。然而，1336和712个RNA分别在内皮素-1或胰岛素诱导的总RNA和/或多核糖体RNA的表达中具有> 1.25倍的显著变化，其中与35%的内皮素-1响应性转录物和与56%的胰岛素响应性转录物相似的转录物受到抑制性调节。已建立的蛋白质招募到多核糖体的mRNA的胰岛素，49个已知的TOP mRNA与进一步的15个可能的TOP mRNA，但49个没有可识别的TOP序列或其他一致的功能在5 '非翻译区。结论：内皮素-1，而不是胰岛素，大大影响全球的转录表达，以促进心肌细胞肥大。对RNA募集到多聚体的影响是微妙的，内皮素-1和胰岛素对特定转录物的影响不同。此外，尽管胰岛素促进TOP mRNA向心肌细胞多聚体的募集，但并非所有募集的mRNA都是TOP mRNA。
Background: Changes in cellular phenotype result from underlying changes in mRNA transcription and translation. Endothelin-1 stimulates cardiomyocyte hypertrophy with associated changes in mRNA/protein expression and an increase in the rate of protein synthesis. Insulin also increases the rate of translation but does not promote overt cardiomyocyte hypertrophy. One mechanism of translational regulation is through 5 ' terminal oligopyrimidine tracts (TOPs) that, in response to growth stimuli, promote mRNA recruitment to polysomes for increased translation. TOP mRNAs include those encoding ribosomal proteins, but the full panoply remains to be established. Here, we used microarrays to compare the effects of endothelin-1 and insulin on the global transcriptome of neonatal rat cardiomyocytes, and on mRNA recruitment to polysomes (i.e. the translatome).Results: Globally, endothelin-1 and insulin (1 h) promoted > 1.5-fold significant (false discovery rate < 0.05) changes in expression of 341 and 38 RNAs, respectively. For these transcripts with this level of change there was little evidence of translational regulation. However, 1336 and 712 RNAs had > 1.25-fold significant changes in expression in total and/or polysomal RNA induced by endothelin-1 or insulin, respectively, of which similar to 35% of endothelin-1-responsive and similar to 56% of insulin-responsive transcripts were translationally regulated. Of mRNAs for established proteins recruited to polysomes in response to insulin, 49 were known TOP mRNAs with a further 15 probable/possible TOP mRNAs, but 49 had no identifiable TOP sequences or other consistent features in the 5 ' untranslated region.Conclusions: Endothelin-1, rather than insulin, substantially affects global transcript expression to promote cardiomyocyte hypertrophy. Effects on RNA recruitment to polysomes are subtle, with differential effects of endothelin-1 and insulin on specific transcripts. Furthermore, although insulin promotes recruitment of TOP mRNAs to cardiomyocyte polysomes, not all recruited mRNAs are TOP mRNAs.