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首页> 外文期刊>Cellular Signalling >Identification of the general transcription factor Yin Yang 1 as a novel and specific binding partner for S6 Kinase 2
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Identification of the general transcription factor Yin Yang 1 as a novel and specific binding partner for S6 Kinase 2

机译：鉴定通用转录因子Yin Yang 1作为S6激酶2的新型特异性结合伴侣

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S6 kinase is a member of the AGC family of serine/threonine kinases and plays a key role in diverse cellular processes including cell growth and metabolism. Although, the high degree of homology between S6K family members (S6K1 and S6K2) in kinase and kinase-extension domains, the two proteins are highly divergent in the N- and C-terminal regulatory regions, hinting at differential regulation, downstream signalling and cellular function. Deregulated signalling via S6Ks has been linked to various human pathologies, such as diabetes and cancer. Therefore, S6K has emerged as a promising target for drug development. Much of what we know about S6K signalling in health and disease comes from studies of S6K1, as molecular cloning of this isoform was reported a decade earlier than S6K2. In this study, we report for the first time, the identification of the general transcription factor Yin Yang 1 (YY1) as a novel and specific binding partner of S6K2, but not S6K1. The interaction between YY1 and S6K2 was demonstrated by co-immunoprecipitation of transiently overexpressed and endogenous proteins in a number of cell lines, including HEK293, MCF7 and U937. Furthermore, direct association between S6K2 and YY1 was demonstrated by GST pull-down assay using recombinant proteins. A panel of deletion mutants was used to show that the C-terminal regulatory region of S6K2 mediates the interaction with YY1. Interestingly, the complex formation between S6K2 and YY1 can be detected in serum-starved cells, but the interaction is strongly induced in response to mitogenic stimulation. The induction of S6K2/YY1 complex formation in response to serum stimulation is abolished by pre-treatment of cells with the mTOR inhibitor, rapamycin. Furthermore, mTOR is also detected in complex with YY1 and S6K2 in serum-stimulated cells. We utilized size exclusion chromatography along with co-immunoprecipitation analysis to demonstrate the existence of the mTOR/S6K2/YY1 complex in high molecular weight fractions, which might also involve other cellular proteins. The physiological significance of the mTOR/S6K2/YY1 complex, which is induced in response to mitogenic stimulation, remains to be further investigated.
机译：S6激酶是AGC丝氨酸/苏氨酸激酶家族的成员，在包括细胞生长和代谢在内的多种细胞过程中起着关键作用。尽管在激酶和激酶扩展域中，S6K家族成员（S6K1和S6K2）之间具有高度同源性，但这两种蛋白在N和C末端调节区差异很大，提示差异调节，下游信号传导和细胞功能。通过S6K进行的信号转导失调已与各种人类疾病（例如糖尿病和癌症）相关联。因此，S6K已经成为药物开发的有希望的目标。我们对健康和疾病中S6K信号的了解很多来自S6K1的研究，因为据报道这种同工型的分子克隆比S6K2早十年。在这项研究中，我们首次报告了将通用转录因子阴阳1（YY1）鉴定为S6K2的新型特异性结合伴侣，但未鉴定出S6K1。 YY1和S6K2之间的相互作用通过在多种细胞系（包括HEK293，MCF7和U937）中瞬时过表达和内源性蛋白质的共免疫沉淀来证明。此外，通过使用重组蛋白的GST下拉测定法证明了S6K2和YY1之间的直接缔合。使用一组缺失突变体来显示S6K2的C末端调节区介导与YY1的相互作用。有趣的是，可以在血清饥饿的细胞中检测到S6K2和YY1之间的复合物形成，但是在促有丝分裂刺激中强烈诱导了相互作用。通过用mTOR抑制剂雷帕霉素预处理细胞，可以消除对血清刺激引起的S6K2 / YY1复合物形成的诱导。此外，在血清刺激的细胞中还检测到mTOR与YY1和S6K2复合。我们利用尺寸排阻色谱法和免疫共沉淀分析来证明mTOR / S6K2 / YY1复合物在高分子量组分中的存在，这也可能涉及其他细胞蛋白。响应有丝分裂刺激而诱导的mTOR / S6K2 / YY1复合物的生理学意义有待进一步研究。

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