University of Dundee, Scotland, UK.
Biochem J. 2011 Feb 1;433(3):515-25. doi: 10.1042/BJ20101562.
Compounds that inhibit signalling upstream of ERK (extracellular-signal-regulated kinase) are promising anticancer therapies, motivating research to define how this pathway promotes cancers. In the present study, we show that human capicúa represses mRNA expression for PEA3 (polyoma enhancer activator 3) Ets transcription factors ETV1, ETV4 and ETV5 (ETV is Ets translocation variant), and this repression is relieved by multisite controls of capicúa by ERK, p90(RSK) (p90 ribosomal S6 kinase) and 14-3-3 proteins. Specifically, 14-3-3 binds to p90(RSK)-phosphorylated Ser¹⁷³ of capicúa thereby modulating DNA binding to its HMG (high-mobility group) box, whereas ERK phosphorylations prevent binding of a C-terminal NLS (nuclear localization sequence) to importin α4 (KPNA3). ETV1, ETV4 and ETV5 mRNA levels in melanoma cells are elevated by siRNA (small interfering RNA) knockdown of capicúa, and decreased by inhibiting ERK and/or expressing a form of capicúa that cannot bind to 14-3-3 proteins. Capicúa knockdown also enhances cell migration. The findings of the present study give further mechanistic insights into why ETV1 is highly expressed in certain cancers, indicate that loss of capicúa can desensitize cells to the effects of ERK pathway inhibitors, and highlight interconnections among growth factor signalling, spinocerebellar ataxias and cancers.
抑制 ERK（细胞外信号调节激酶）上游信号的化合物是很有前途的抗癌疗法，这促使人们研究如何促进癌症发展。在本研究中，我们表明，人 Capicúa 抑制 PEA3（多瘤增强激活物 3）Ets 转录因子 ETV1、ETV4 和 ETV5（ETV 是 Ets 易位变体）的 mRNA 表达，这种抑制作用通过 ERK、p90(RSK)（p90 核糖体 S6 激酶）和 14-3-3 蛋白对 Capicúa 的多部位控制得到缓解。具体而言，14-3-3 结合到 Capicúa 的 p90(RSK)-磷酸化 Ser¹⁷³，从而调节其 HMG（高迁移率族）盒的 DNA 结合，而 ERK 磷酸化阻止 C 端 NLS（核定位序列）与 importin α4（KPNA3）结合。黑色素瘤细胞中 ETV1、ETV4 和 ETV5 的 mRNA 水平通过 Capicúa 的 siRNA（小干扰 RNA）敲低而升高，并通过抑制 ERK 和/或表达不能与 14-3-3 蛋白结合的 Capicúa 形式而降低。Capicúa 敲低也增强了细胞迁移。本研究的发现进一步深入了解了为什么 ETV1 在某些癌症中高度表达，表明 Capicúa 的缺失可以使细胞对 ERK 途径抑制剂的作用脱敏，并突出了生长因子信号、脊髓小脑共济失调和癌症之间的相互联系。
