Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
Life Sci Alliance. 2022 Mar 22;5(7). doi: 10.26508/lsa.202101345. Print 2022 Mar.
All-trans retinoic acid (ATRA) increases the sensitivity to unfolded protein response in differentiating leukemic blasts. The downstream transcriptional factor of PERK, a major arm of unfolded protein response, regulates muscle differentiation. However, the role of growth arrest and DNA damage-inducible protein 34 (GADD34), one of the downstream factors of PERK, and the effects of ATRA on GADD34 expression in muscle remain unclear. In this study, we identified ATRA increased the GADD34 expression independent of the PERK signal in the gastrocnemius muscle of mice. ATRA up-regulated GADD34 expression through the transcriptional activation of gene via inhibiting the interaction of homeobox Six1 and transcription co-repressor TLE3 with the MEF3-binding site on the gene promoter in skeletal muscle. ATRA also inhibited the interaction of TTP, which induces mRNA degradation, with AU-rich element on mRNA via p-38 MAPK, resulting in the instability of mRNA. Overexpressed GADD34 in C2C12 cells changes the type of myosin heavy chain in myotubes. These results suggest ATRA increases GADD34 expression via transcriptional and post-transcriptional regulation, which changes muscle fiber type.
全反式维甲酸（ATRA）增加了分化白血病细胞对未折叠蛋白反应的敏感性。未折叠蛋白反应的主要分支 PERK 的下游转录因子调节肌肉分化。然而，PERK 的下游因子之一生长停滞和 DNA 损伤诱导蛋白 34（GADD34）的作用以及 ATRA 对肌肉中 GADD34 表达的影响尚不清楚。在这项研究中，我们发现 ATRA 可在不依赖 PERK 信号的情况下增加小鼠腓肠肌中的 GADD34 表达。ATRA 通过抑制同源盒 Six1 和转录共抑制因子 TLE3 与肌细胞中基因启动子上 MEF3 结合位点的相互作用，通过转录激活基因，上调 GADD34 表达。ATRA 还通过 p-38 MAPK 抑制 TTP（诱导 mRNA 降解）与基因 mRNA 上的 AU 富含元件的相互作用，导致基因 mRNA 的不稳定性。在 C2C12 细胞中过表达 GADD34 会改变肌管中的肌球蛋白重链类型。这些结果表明，ATRA 通过转录和转录后调控增加 GADD34 表达，从而改变肌肉纤维类型。
