紐約大學(xué)醫(yī)學(xué)院的 Mark Philips領(lǐng)導(dǎo)的研究組最近發(fā)現(xiàn)了調(diào)控K-Ras基因表達(dá)的新機制,，該機制能引發(fā)細(xì)胞自毀，因此將有潛力成為新一代的抗癌藥物靶標(biāo),。
Ras癌基因參與人類腫瘤的發(fā)生發(fā)展，最初是在急性轉(zhuǎn)化性逆轉(zhuǎn)錄病毒實驗中從Harvey,、Kirsten兩株大鼠肉瘤病毒中克隆出來的轉(zhuǎn)化基因,，自1982年Weinberg等人發(fā)現(xiàn)人的膀胱癌細(xì)胞中有活化的H-ras基因后，引起了人們對ras癌基因在人類腫瘤發(fā)生發(fā)展過程中所起的作用的極大關(guān)注,。
ras基因家族與人類腫瘤相關(guān)的基因有三種——H-ras,、K-ras和N-ras，分別定位在11,、12和1號染色體上,。其中，K-Ras則對人類癌癥影響最大,，它好像分子開關(guān)：當(dāng)正常時能控制調(diào)控細(xì)胞生長的路徑,；發(fā)生異常時，則導(dǎo)致細(xì)胞持續(xù)生長,，并阻止細(xì)胞自我毀滅,。
新的研究中，研究人員發(fā)現(xiàn)K-Ras蛋白并不是永遠(yuǎn)位于細(xì)胞膜上,，它的位置受到蛋白激酶 C (protein kinase C,，PKC) 的控制。他們發(fā)現(xiàn) PKC 使磷酸分子與 K-Ras結(jié)合即磷酸化,，,，這種磷酸化過程導(dǎo)致K-Ras與細(xì)胞膜的結(jié)合減弱而改變位置，并移至內(nèi)質(zhì)網(wǎng)、高爾基體和粒線體等位置,。這篇文章發(fā)表在剛剛發(fā)版的Mol Cell上,。.
通過細(xì)胞培養(yǎng)實驗，研究人員發(fā)現(xiàn)磷酸化的 K-Ras 具高毒性,，會促進(jìn)細(xì)胞的自殺——這與以往認(rèn)為致癌基因?qū)е录?xì)胞生長失控,、抑制死亡是完全相反的。該研究揭示出,，如果能找出使K-Ras 磷酸化的方式,，將可加速因ras致癌基因引發(fā)的腫瘤細(xì)胞發(fā)生自殺。
最對老鼠腫瘤細(xì)胞進(jìn)行分析時,，研究人員發(fā)現(xiàn),，當(dāng)K-Ras 無法磷酸化時，具抗腫瘤效用的 byrostatin 藥物即無法產(chǎn)生作用,。這意味著這種藥物的抗腫瘤功能確實是通過磷酸化機制進(jìn)行的,。因此，促進(jìn)K-Ras磷酸化的藥物將成為治療肺癌,、胰臟癌和其它癌癥的一個新希望,。
原文英文下載：另存為下載（PDF文件）.
原始出處：
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.
相關(guān)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. 簡介（Ras領(lǐng)域研究國際權(quán)威，近來興趣在高爾基體的Ras信號）
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.
