纽约大学医学院的 Mark Philips领导的研究组最近发现了调控K-Ras基因表达的新机制，该机制能引发细胞自毁，因此将有潜力成为新一代的抗癌药物靶标。
Ras癌基因参与人类肿瘤的发生发展，最初是在急性转化性逆转录病毒实验中从Harvey、Kirsten两株大鼠肉瘤病毒中克隆出来的转化基因，自1982年Weinberg等人发现人的膀胱癌细胞中有活化的H-ras基因后，引起了人们对ras癌基因在人类肿瘤发生发展过程中所起的作用的极大关注。
ras基因家族与人类肿瘤相关的基因有三种——H-ras、K-ras和N-ras，分别定位在11、12和1号染色体上。其中，K-Ras则对人类癌症影响最大，它好像分子开关：当正常时能控制调控细胞生长的路径；发生异常时，则导致细胞持续生长，并阻止细胞自我毁灭。
新的研究中，研究人员发现K-Ras蛋白并不是永远位于细胞膜上，它的位置受到蛋白激酶 C (protein kinase C，PKC) 的控制。他们发现 PKC 使磷酸分子与 K-Ras结合即磷酸化，，这种磷酸化过程导致K-Ras与细胞膜的结合减弱而改变位置，并移至内质网、高尔基体和粒线体等位置。这篇文章发表在刚刚发版的Mol Cell上。.
通过细胞培养实验，研究人员发现磷酸化的 K-Ras 具高毒性，会促进细胞的自杀——这与以往认为致癌基因导致细胞生长失控、抑制死亡是完全相反的。该研究揭示出，如果能找出使K-Ras 磷酸化的方式，将可加速因ras致癌基因引发的肿瘤细胞发生自杀。
最对老鼠肿瘤细胞进行分析时，研究人员发现，当K-Ras 无法磷酸化时，具抗肿瘤效用的 byrostatin 药物即无法产生作用。这意味着这种药物的抗肿瘤功能确实是通过磷酸化机制进行的。因此，促进K-Ras磷酸化的药物将成为治疗肺癌、胰脏癌和其它癌症的一个新希望。
原文英文下载：另存为下载（PDF文件）.
原始出处：
Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Perez de Castro I, Li C, Thompson CB, Cox AD, Philips MR. PKC Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association with Bcl-Xl on Mitochondria and Induces Apoptosis.
Mol Cell. 2006 Feb 17;21(4):481-93.
相关研究成果：
Quatela SE, Philips MR. Ras signaling on the Golgi.
Curr Opin Cell Biol. 2006 Feb 17
Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Perez de Castro I, Li C, Thompson CB, Cox AD, Philips MR. PKC Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association with Bcl-Xl on Mitochondria and Induces Apoptosis.
Mol Cell. 2006 Feb 17;21(4):481-93.
Mor A, Philips MR. Compartmentalized Ras/MAPK Signaling.
Annu Rev Immunol. 2006 Jan 16;
Goodwin JS, Drake KR, Rogers C, Wright L, Lippincott-Schwartz J, Philips MR, Kenworthy AK. Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway.
J Cell Biol. 2005 Jul 18;170(2):261-72.
Perez de Castro I, Bivona TG, Philips MR, Pellicer A. Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus.
Mol Cell Biol. 2004 Apr;24(8):3485-96.
Mark R. Philips M.D. 简介（Ras领域研究国际权威，近来兴趣在高尔基体的Ras信号）
Processing and membrane targeting of GTPases.
Mark R. Philips M.D.
Professor of Medicine, Cell Biology and Pharmacology
Departments of Medicine (Rheumatology) and Cell Biology and Pharmacology
Research Summary
Our laboratory is primarily interested in the cell biology of GTPases. GTPases are ubiquitous elements of signaling pathways, including those regulating cell growth and differentiation. Virtually all cellular processes utilize GTPases as regulatory elements including processes that control the immune response. Thus, although our work has immediate relevance to cancer, insights from our studies may be relevant to a wide variety of human diseases including inflammatory and autoimmune disorders.
The protooncogene ras and closely related GTPases are among a class of proteins that are synthesized as soluble molecules in the cytosol and are then targeted to membranes by a series of posttranslational modifications of a C-terminal CAAX sequence that includes prenylation, proteolysis, and carboxyl methylation. Of these modifications, only carboxyl methylation is reversible and may therefore have a signaling function. We therefore focused on the enzyme that catalyzes this modification, prenylcysteine carboxyl methyltransferase, and recently cloned its gene.
Prenylcysteine carboxyl methyltransferase proved to be a multiple membrane spanning protein that is expressed in ER and Golgi but not plasma membrane (see figure). This observation was surprising since it implied that ras, synthesized in the cytosol and destined for the plasma membrane, must make a detour to the ER to complete processing. The ER processing of ras led us to hypothesize that ras is transported to plasma membrane via the vesicular transport system. Using green fluorescent protein-tagged ras proteins we showed that this model is correct. We also showed that carboxyl methylation is required for vesicular transport of ras. We hope to exploit this previously unappreciated aspect of ras biology to develop novel anticancer therapies.
In more recent work we have tested the hypothesis that intracellular ras can be activated and regulate signaling pathways and proved it correct. We accomplished this by developing a novel fluorescent probe that reports when and where Ras becomes activated in living cells. We consider our probe for activated ras a prototyped of a class of molecules that can serve as fluorescent reporters of signaling events in living cells and thereby elucidate many previously inaccessible aspects of signal transduction.
Related Images
Image 1 Expression in COS-1 cells of GFP-tagged prenylcysteine carboxyl methyltransferase (pcCMT), one of the three enzymes that modifies the product of the Ras oncogene. Note that expression is restricted to the endoplasmic reticulum (ER).
Research Information
Research Interests Processing and membrane targeting of GTPases.
Research Keywords Cancer, Signal Transduction, GTPases, Ras, Protein Prenylation, Protein Methylation.
