Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response.
Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response.
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DOI：
10.1016/j.yjmcc.2012.01.017
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发表时间：
2012-05
影响因子：
5
通讯作者：
Glembotski CC
中科院分区：
文献类型：
--
作者：
Belmont PJ;Chen WJ;Thuerauf DJ;Glembotski CC
内质网应激的一个节点调节因子是转录因子ATF6，它在体内被缺血激活并保护心脏免受缺血损伤。为了探索ATF6介导的心脏保护机制，对ATF6转基因（TG）小鼠的心脏RNA进行了全基因组microRNA （miRNA）阵列分析。该阵列确定了13个atf6调控的mirna，其中8个下调，表明它们可能有助于提高其mrna水平。下调的mirna，包括miR-455，预计靶向45种mrna，我们之前通过微阵列分析显示，这些mrna在心脏中被ATF6上调。miR-455的靶点之一是钙网蛋白（Calr），它在病理性心脏中上调，在那里它调节肥厚生长，潜在地减少病理的影响。为了验证miR-455的作用，我们发现在小鼠心脏中，ATF6增加了Calr蛋白。在培养的心肌细胞中，内质网应激源、tunicamycin或编码活化ATF6的腺病毒处理可降低miR-455并增加Calr水平，这与体内ATF6对miR-455和Calr的影响一致。此外，转染人工合成前体pre - mir -455的培养心肌细胞降低了Calr水平，而转染反义的anti - mir -455则增加了Calr水平。本研究结果提示内质网应激可通过atf6介导的微rna水平变化调控基因表达。此外，这些发现支持了ATF6介导的miR-455下调增加Calr表达的假设，这可能有助于ATF6在心脏中的保护作用。
A nodal regulator of endoplasmic reticulum stress is the transcription factor, ATF6, which is activated by ischemia and protects the heart from ischemic damage, in vivo. To explore mechanisms of ATF6-mediated protection in the heart, a whole-genome microRNA (miRNA) array analysis of RNA from the hearts of ATF6 transgenic (TG) mice was performed. The array identified 13 ATF6-regulated miRNAs, eight of which were downregulated, suggesting that they could contribute to increasing levels of their mRNAs. The down-regulated miRNAs, including miR-455, were predicted to target 45 mRNAs that we had previously shown by microarray analysis to be up-regulated by ATF6 in the heart. One of the miR-455 targets was calreticulin (Calr), which is up-regulated in the pathologic heart, where it modulates hypertrophic growth, potentially reducing the impact of the pathology. To validate the effects of miR-455, we showed that Calr protein was increased by ATF6 in mouse hearts, in vivo. In cultured cardiac myocytes, treatment with the ER stressor, tunicamycin, or with adenovirus encoding activated ATF6 decreased miR-455 and increased Calr levels, consistent with the effects of ATF6 on miR-455 and Calr, in vivo. Moreover, transfection of cultured cardiac myocytes with a synthetic precursor, premiR-455, decreased Calr levels, while transfection with an antisense, antimiR-455, increased Calr levels. The results of this study suggest that ER stress can regulate gene expression via ATF6-mediated changes in micro-RNA levels. Moreover, these findings support the hypothesis that ATF6-mediated down-regulation of miR-455 augments Calr expression, which may contribute to the protective effects of ATF6 in the heart.
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影响因子：
12.3
作者：
Ruepp A;Kowarsch A;Schmidl D;Buggenthin F;Brauner B;Dunger I;Fobo G;Frishman G;Montrone C;Theis FJ
通讯作者：
Theis FJ
影响因子：
4.8
作者：
Seo, Hye-Young;Kim, Mi-Kyung;Lee, In-Kyu
通讯作者：
Lee, In-Kyu
DOI：
10.1152/ajpheart.1997.272.1.h168
发表时间：
1997-01-01
影响因子：
4.8
作者：
Tsutsui, H;Ishibashi, Y;Takeshita, A
通讯作者：
Takeshita, A
影响因子：
7.8
作者：
Mesaeli, N;Nakamura, K;Zvaritch, E;Dickie, P;Dziak, E;Krause, K H;Opas, M;MacLennan, D H;Michalak, M
通讯作者：
Michalak, M
影响因子：
14.9
作者：
Griffiths-Jones S;Grocock RJ;van Dongen S;Bateman A;Enright AJ
通讯作者：
Enright AJ