miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage

被引：31

作者：

Bluhm, Bjorn ^{[1
,2
]}

Ehlen, Harald W. A. ^{[1
,2
]}

Holzer, Tatjana ^{[1
,2
]}

Georgieva, Veronika S. ^{[1
,2
]}

Heilig, Juliane ^{[3
,4
]}

Pitzler, Lena ^{[1
,2
]}

Etich, Julia ^{[1
,2
]}

Bortecen, Toman ^{[1
,2
]}

Frie, Christian ^{[1
,2
]}

Probst, Kristina ^{[1
,2
]}

Niehoff, Anja ^{[3
,4
]}

Belluoccio, Daniele ^{[5
,6
]}

Van den Bergen, Jocelyn ^{[5
,7
]}

Brachvogel, Bent ^{[1
,2
,4
]}

机构：

[1] Univ Cologne, Med Fac, Dept Pediat & Adolescent Med, Expt Neonatol, D-50931 Cologne, Germany

[2] Univ Cologne, Med Fac, Ctr Biochem, D-50931 Cologne, Germany

[3] German Sport Univ Cologne, Inst Biomech & Orthopaed, D-50931 Cologne, Germany

[4] Univ Cologne, CCMB, D-50931 Cologne, Germany

[5] Univ Melbourne, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[6] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia

[7] Univ Melbourne, Dept Pediat, Parkville, Vic 3052, Australia

来源：

DEVELOPMENT | 2017年 / 144卷 / 19期

关键词：

MEK; Cartilage; MAPK; miR-322; CRISPR; Stabilization; CHONDROCYTE PROLIFERATION; ABLATION; COLLAGEN; CELLS;

D O I：

10.1242/dev.148429

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cartilage originates from mesenchymal cell condensations that differentiate into chondrocytes of transient growth plate cartilage or permanent cartilage of the articular joint surface and trachea. MicroRNAs fine-tune the activation of entire signaling networks and thereby modulate complex cellular responses, but so far only limited data are available on miRNAs that regulate cartilage development. Here, we characterize a miRNA that promotes the biosynthesis of a key component in the RAF/MEK/ERK pathway in cartilage. Specifically, by transcriptome profiling we identified miR-322 to be upregulated during chondrocyte differentiation. Among the various miR-322 target genes in the RAF/MEK/ERK pathway, only Mek1 was identified as a regulated target in chondrocytes. Surprisingly, an increased concentration of miR-322 stabilizes Mek1 mRNA to raise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation of miR322 in mice linked the loss of miR-322 to decreased MEK1 levels and to increased RAF/MEK/ERK pathway activation. Such mice died perinatally due to tracheal growth restriction and respiratory failure. Hence, a single miRNA can stimulate the production of an inhibitory component of a central signaling pathway to impair cartilage development.

引用

页码：3562 / 3577

页数：16

共 41 条

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