Identification of a co-activator that links growth factor signalling to c-Jun/AP-1 activation
Identification of a co-activator that links growth factor signalling to c-Jun/AP-1 activation
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DOI：
10.1038/ncb2098
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发表时间：
2010-10-01
影响因子：
21.3
通讯作者：
Behrens, Axel
中科院分区：
文献类型：
--
作者：
Davies, Clare C.;Chakraborty, Atanu;Behrens, Axel
AP-1转录因子c-Jun对于许多细胞类型中的细胞增殖是必需的，但是生长因子和c-Jun活化之间的分子联系一直是谜。在这项研究中，我们确定了一个以前未表征的环结构域的蛋白质，RACO-1（环结构域AP-1共激活因子-1），作为一个c-Jun共激活因子，是由生长因子信号调节。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活化是必要的和充分的。生长因子介导的AP-1刺激归因于MEK/ERK依赖的RACO-1蛋白的稳定。MEK/ERK通路的刺激强烈促进RACO-1的Lys 63连接的泛素化，其拮抗相同的Lys残基的Lys 48连接的降解性自身泛素化。RACO-1耗竭降低了细胞增殖，并降低了几种生长相关的AP-1靶基因的表达，如cdc 2，cyclinD 1和hb-egf。此外，RACO-1的转基因过表达增强了由异常Wnt信号传导引发的肠道肿瘤形成，并与结肠过度增殖中的致癌Ras合作。因此，RACO-1是一种将c-Jun与生长因子信号传导联系起来的共激活剂，并且对于AP-1在增殖中的功能至关重要。
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.