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首页> 外文期刊>Nature cell biology >Identification of a co-activator that links growth factor signalling to c-Jun/AP-1 activation.
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Identification of a co-activator that links growth factor signalling to c-Jun/AP-1 activation.

机译:鉴定将生长因子信号传导与c-Jun / AP-1激活关联的共激活剂。

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摘要

The AP-1 transcription factor c-Jun is essential for cellular proliferation in many cell types, but the molecular link between growth factors and c-Jun activation has been enigmatic. In this study we identify a previously uncharacterized RING-domain-containing protein, RACO-1 (RING domain AP-1 co-activator-1), as a c-Jun co-activator that is regulated by growth factor signalling. RACO-1 interacted with c-Jun independently of amino-terminal phosphorylation, and was both necessary and sufficient for c-Jun/AP-1 activation. Growth factor-mediated stimulation of AP-1 was attributable to MEK/ERK-dependent stabilization of RACO-1 protein. Stimulation of the MEK/ERK pathway strongly promoted Lys 63-linked ubiquitylation of RACO-1, which antagonized Lys 48-linked degradative auto-ubiquitylation of the same Lys residues. RACO-1 depletion reduced cellular proliferation and decreased expression of several growth-associated AP-1 target genes, such as cdc2, cyclinD1 and hb-egf. Moreover, transgenic overexpression of RACO-1 augmented intestinal tumour formation triggered by aberrant Wnt signalling and cooperated with oncogenic Ras in colonic hyperproliferation. Thus RACO-1 is a co-activator that links c-Jun to growth factor signalling and is essential for AP-1 function in proliferation.
机译:AP-1转录因子c-Jun对于许多细胞类型的细胞增殖都是必不可少的,但是生长因子和c-Jun激活之间的分子联系一直是谜。在这项研究中,我们确定了以前未知的含RING域的蛋白RACO-1(RING域AP-1共同激活剂1)作为受生长因子信号调节的c-Jun共同激活剂。 RACO-1与c-Jun相互作用独立于氨基末端磷酸化,并且对于c-Jun / AP-1激活既必要又充分。生长因子介导的AP-1刺激可归因于RAK-1蛋白的MEK / ERK依赖性稳定。 MEK / ERK途径的刺激强烈促进了RACO-1的Lys 63连接的泛素化,它拮抗了Lys 48连接的相同Lys残基的降解性自体泛素化。 RACO-1耗竭减少了细胞增殖,并降低了几种与生长相关的AP-1靶基因(如cdc2,cyclinD1和hb-egf)的表达。此外,转基因的过表达RACO-1增加了异常Wnt信号触发的肠道肿瘤形成,并在结肠过度增殖中与致癌Ras协同作用。因此,RACO-1是将c-Jun连接至生长因子信号传导的辅助激活剂,并且对于AP-1在增殖中的功能至关重要。

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