文章：

7号染色体开放阅读框41基因通过调节TPA诱导的信号传导促进白血病巨核细胞分化的新功能

Novel function of the chromosome 7 open reading frame 41 gene to promote leukemic megakaryocyte differentiation by modulating TPA-induced signaling

原文发布日期：2014-03-28

DOI: 10.1038/bcj.2014.18

类型: Original Article

开放获取: 是

英文摘要：

12-O-tetradecanoylphorbol-13-acetate (TPA) activates multiple signaling pathways, alters gene expression and causes leukemic cell differentiation. How TPA-induced genes contribute to leukemic cell differentiation remains elusive. We noticed that chromosome 7 open reading frame 41 (C7ORF41) was a TPA-responsive gene and its upregulation concurred with human megakaryocyte differentiation. In K562 cells, ectopic expression of C7ORF41 significantly increased CD61 expression, enhanced ERK and JNK signaling, and upregulated RUNX1 and FLI1, whereas C7ORF41 knockdown caused an opposite phenotype. These observations suggest that C7ORF41 may promote megakaryocyte differentiation partially through modulating ERK and JNK signaling that leads to upregulation of RUNX1 and FLI1. In supporting this, C7ORF41 overexpression rescued megakaryocyte differentiation blocked by ERK inhibition while JNK inhibition abrogated the upregulation of FLI1 by C7ORF41. Furthermore, we found that Y34F mutant C7ORF41 inhibited megakaryocyte differentiation. nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was the major activator of C7ORF41 that in turn repressed NF-κB activity by inhibiting its phosphorylation at serine 536, while MAPK/ERK was the potent repressor of C7ORF41. Finally, we showed that C7ORF41 knockdown in mouse fetal liver cells impaired megakaryocyte differentiation. Taken together, we have identified the function of a novel gene C7ORF41 that forms interplaying regulatory network in TPA-induced signaling and promotes leukemic and normal megakaryocyte differentiation.

摘要翻译： 

12-氧-十四烷酰佛波醇-13-乙酸酯（TPA）能激活多条信号通路、改变基因表达并诱导白血病细胞分化。然而TPA诱导基因如何促进白血病细胞分化的机制尚不明确。本研究发现染色体7开放阅读框41（C7ORF41）是TPA应答基因，其上调与人巨核细胞分化同步。在K562细胞中，异位表达C7ORF41可显著提升CD61表达水平，增强ERK和JNK信号通路活性，上调RUNX1和FLI1基因；而敲低C7ORF41则呈现相反表型。这些结果表明C7ORF41可能通过调控ERK和JNK信号通路促进RUNX1和FLI1表达，进而部分推动巨核细胞分化。支持这一机制的是：C7ORF41过表达能挽救被ERK抑制阻断的巨核细胞分化，而JNK抑制则消除了C7ORF41对FLI1的上调作用。此外，我们发现Y34F突变型C7ORF41会抑制巨核细胞分化。核因子κB（NF-κB）是C7ORF41的主要激活因子，而C7ORF41又通过抑制NF-κB丝氨酸536位点的磷酸化负反馈调控其活性；MAPK/ERK则是C7ORF41的有效抑制因子。最后，我们证实敲低小鼠胎肝细胞中的C7ORF41会损害巨核细胞分化。综上所述，我们揭示了一个新基因C7ORF41的功能：它在TPA诱导的信号通路中构建相互作用的调控网络，并促进白血病细胞及正常巨核细胞的分化。

原文链接：

Novel function of the chromosome 7 open reading frame 41 gene to promote leukemic megakaryocyte differentiation by modulating TPA-induced signaling