上海药物研究所药物发现与设计中心(DDDC)罗成副研究员参与美国弗吉尼亚联邦大学医学院Sarah Spiegel教授“鞘氨醇磷酸酯（sphingosine-1-phosphate, S1P）调控机制的研究”，取得重大突破，研究论文于2009年9月4日发表在《科学》（Science）杂志上（Science 2009, 325: 1254-1257）。
该研究首次发现了S1P是一种组蛋白去乙酰化酶(HDAC)生理调节因子，HDAC是S1P在细胞内的直接靶标，S1P通过HDAC调控基因的表达，具有调控基因表达的新功能。该研究还阐明了S1P调控基因表达的机制。S1P最初发现与细胞生长的调节有关，它是一种存在于细胞核中具有生物活性的脂质信使，由2型鞘氨醇激酶（SphK2）产生。SphK2选择性聚集在编码细胞周期蛋白依赖性激酶抑制剂p21或转录调节因子c-fos的基因启动子上。S1P通过特异性结合HDAC1和HDAC2，抑制其活性，进而保护组氨酸末端赖氨酸不被去乙酰化，从而提高组蛋白H3乙酰化的程度，促进转录。因此， S1P在调控基因表达中的新机制将为发展新型HDAC抑制剂，开发抗肿瘤及免疫疾病的新型药物奠定了基础。
在该研究中，上海药物研究所研究人员利用分子模拟方法预测组蛋白去乙酰化酶(HDAC)可能是S1P的作用靶标，并预测了两者间的结合模式和关键作用残基，进而精确预测出S1P与HDAC的亲合能力与HDAC现有抑制剂SAHA相当。这些理论预测结果为该研究提供了关键的线索，并在实验上被Sarah Spiegel等证实。
该研究综合运用分子模拟和实验的手段研究S1P调控机制的生物学问题，表明计算与实验的有机结合，可作为一种重要的研究策略，为研究生命科学其它相关复杂问题提供了一种可靠的思路。（生物谷Bioon.com）
生物谷推荐原始出处：
Science 4 September 2009:DOI: 10.1126/science.1176709
Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate
Nitai C. Hait,1 Jeremy Allegood,1 Michael Maceyka,1 Graham M. Strub,1 Kuzhuvelil B. Harikumar,1 Sandeep K. Singh,1 Cheng Luo,2,3 Ronen Marmorstein,2 Tomasz Kordula,1 Sheldon Milstien,4 Sarah Spiegel1,*
The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) can act intracellularly independently of its cell surface receptors through unknown mechanisms. Sphingosine kinase 2 (SphK2), one of the isoenzymes that generates S1P, was associated with histone H3 and produced S1P that regulated histone acetylation. S1P specifically bound to the histone deacetylases HDAC1 and HDAC2 and inhibited their enzymatic activity, preventing the removal of acetyl groups from lysine residues within histone tails. SphK2 associated with HDAC1 and HDAC2 in repressor complexes and was selectively enriched at the promoters of the genes encoding the cyclin-dependent kinase inhibitor p21 or the transcriptional regulator c-fos, where it enhanced local histone H3 acetylation and transcription. Thus, HDACs are direct intracellular targets of S1P and link nuclear S1P to epigenetic regulation of gene expression.
1 Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
2 The Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
4 National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
