Ras癌基因及其负调控因子

       　Ras是70年发现的一组癌基因家族。30多年来的研究证明，Ras癌基因在细胞内信号传递和细胞增殖过程中起着关键和核心作用。癌基因的过量表达不仅是许多恶性肿瘤发病的重要基础，亦与体内许多细胞增殖性疾病（如动脉粥样硬化等）的发病有着密切关系。它还参与体内炎症、免疫、凋亡、迁移、再塑、损伤等许多病理生理过程。许多实验证明抑制Ras癌基因的过量表达，是防治肿瘤和一些严重心血管病的重要途径，为此长期以来，人们致力于探求内源性抑制Ras的靶分子，但是收效甚少。最近我所陈光慧教授及其同人，经过近十年的不懈努力，终于克隆出一种抑制细胞增殖基因--HSG。它不仅可以明显抑制Ras、Raf和MEPK细胞内传递分子的表达，抑制细胞的增殖；而且可以有效遏制高血压、动脉硬化、再狭窄和心血管的再塑的发生，这篇重要论文被发表在最近一期Nature cell biology上。为此Nature编辑部还发表专门评论，提出HSG不仅是一个新的Ras通路负调控因子，而且是细胞增殖通路的一个新的调控点。这一发现不仅在动脉粥样硬化，心功能衰竭和心肌肥厚的发病过程中具有重要意义，对其它细胞和系统亦是重要的提示作用（K.R.Chen & M.Hoshijima. 2004），他们认为HSG基因的发现，对揭示体内新的信号传递通路将可能是一个新的发展趋势。事实上，陈光慧教授及其同仁们的工作已经证明，HSG基因在体内外亦可有效的阻遏肿瘤细胞的增殖、迁移和发生。这是我国科学家在心血管和医学生物学领域的又一重要贡献，是国家863和973心血管研究计划的又一重要成果。为此CMBI全文转载这篇论文及Nature的相关评论。并搜索了一些关于Ras研究的重要文献，作为特别报导，供大家参考，更多的文献，特别是cancer与Ras文献，请在CMBI文献查询中查阅。

 

十年磨一针--陈光慧教授与她的HSG基因
HSG原著论文
K.H. Chen etal. Dysregulation of HSG triggers vascular proliferative disorders
Nature Cell Biology Published online: 22 August 2004 | doi:10.1038/ncb1161
K.H. Chen etal. HSG Supplementary Information
Nature Cell Biology Published online: 22 August 2004 | doi:10.1038/ncb1161
Nature 评论
K.R. Chien & M. Hoshijima, Unravelling Ras signals in cardiovascular disease
Nature Cell Biology Vol6, No9, 2004

总论

• A Ras by Any Other Name
  
• Activation of Mitogen-activated Protein Kinase by Membrane-targeted Raf Chimeras Is Independent of Raf
  
• Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells
  
• Alternative effects of RAS and RAF oncogenes on the proliferation and apoptosis
  
• CalDAG-GEFIII Activation of Ras, R-Ras, and Rap1
  
• Can Regulate the Ras-MAP Kinase Pathway independent of its role in endocytosis
  
• Cell signaling-life or death decisions of ras proteins
  
• Cell surface receptors activate p21-activated kinase 1 via multiple Ras and PI3-kinase-dependent pathways
  
• Compartmentalization of Ras proteins
  
• Control Of Ras Cycling By Ca2+
  
• Crk Activation of JNK via C3G and R-Ras
  
• Distinct Mechanisms of 51 Integrin Activation by Ha-Ras and R-Ras
  
• Distinct Rates of Palmitate Turnover on Membrane-bound Cellular and Oncogenic H-Ras
  
• ephrin bidirectional signals that target Ras and Rho
  
• Exploring environmental causes of altered ras effects
  
• Fine-Tuning the RAS Signaling Pathway
  
• Fk506 Potentiates Ngf-Induced Neurite Outgrowth Via The Ras-Raf-Map Kinase Pathway
  
• Formation of the Ras Dimer Is Essential for Raf-1 Activation
  
• Function of the Rho Family GTPases in Ras-stimulated Raf Activation
  
• GAPs galore! A survey of putative Ras superfamily GTPase activating proteins
  
• G-protein Signaling by a Ras-related Protein
  
• Identification of a Novel Ras-Regulated Proapoptotic Pathway
  
• Increasing Complexity of the Ras Signaling Pathway
  
• INTEGRATION OF CALCIUM AND RAS SIGNALLING
  
• Intersectin Activates Ras But Stimulates Transcription Through An Independent Pathway Involving Jnk
  
• KSR-a MAPK scaffold of the Ras pathway
  
• Life or Death Decisions of Ras Proteins
  
• Mechanical Stress–Induced Heat Shock Protein 70 Expression in VSMC Is Regulated by Rac and Ras
  
• Mechanisms of Ras protein targeting in mammalian cells
  
• Methotrexate and Ras Methylation-A New Trick for an Old Drug
  
• Modulation of Ras-Raf-Extracellular Signal–Regulated Kinase Pathway by Reactive Oxygen Species Is Involved in Cyclic Strain–Induced Early Growth Response-1 Gene Expression in Endothelial Cells
  
• Modulation of the Ras-Raf-MEK-ERK pathway by Ca2+, and Calmodulin
  
• Molecular Perspective-The ras Oncogene
  
• Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras
  
• Oncogenic Ha-Ras Transformation Modulates the Transcription
  
• Oncogenic Ras Leads to Rho Activation by Activating the Mitogen-activated Protein Kinase Pathway
  
• Opposing Roles of Ras Raf Oncogenes and the MEK1 ERK Signaling Module in Regulation of Expression
  
• Promotion and Attenuation of FGF Signaling Through the Ras-MAPK Pathway
  
• Protein-G and G Require Distinct Src-dependent Pathways to Activate Rap1 and Ras
  
• Raf-like Ras-Rap-binding domains in RGS12-and still-life-like signalling proteins
  
• Ras Activation of the Raf Kinase
  
• Ras activation revisited
  
• RAS AND RHO GTPases IN G1-PHASE CELL-CYCLE REGULATION---
  
• Ras and Rho GTPases-A Family Reunion
  
• Ras and Rho regulation of the cell cycle and oncogenesis
  
• Ras family genes
  
• Ras Isoform-Specific Signaling
  
• RAS ONCOGENES-THE FIRST 30 YEARS---
  
• Ras Participates in CpG Oligodeoxynucleotide Signaling through Association with Toll-like Receptor 9
  
• Ras pathway activation
  
• Ras Protects Rb Family Null Fibroblasts from Cell Death
  
• Ras proteins-different signals from different locations
  
• Ras Proteins-Recent Advances and New Functions
  
• Ras redux-rethinking how and where Ras acts
  
• Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP
  
• Ras Regulates The Steady-State Expression Of Matrix Metalloproteinase-In Fibroblasts
  
• Ras Signaling and Transcriptional Synergy at a Flexible Ets-1-Pit-1 Composite DNA Element Is Defined
  
• Ras signalling on the endoplasmic reticulum and the Golgi
  
• Ras signalling-Visualizing Ras signalling in real-time
  
• Ras stimulates DNA topoisomerase II through MEK
  
• Ras–effector interactions
  
• Ras-2000
  
• Ras-dependent cell cycle commitment during G2 phase
  
• Ras-like-GTPase
  
• Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists
  
• Ras-membranse-interation
  
• Ras-RAF--conspiracy-theory
  
• Ras-related and MAPK signalling
  
• Ras-Rho-protein
  
• Regulation of cell cycle molecules by the Ras effector system
  
• Regulation of Ras signaling by the cell cycle
  
• Regulation of Ras Signaling Specificity by Protein Kinase C
  
• Regulation of the p53 pathway by Ras
  
• Rig is a novel Ras-related protein
  
• RJLs-a new family of Ras-related GTP-binding proteins
  
• Roc, a Ras-GTPase domain in complex proteins
  
• Role of Ras and Mapks in TGF signaling
  
• Signal Transduction-IMPlications for Ras-Dependent ERK Signaling
  
• Signaling from Ras to Rac and beyond
  
• Signaling of G12 Family of G Proteins Through a Tyrosine Kinase and a Ras-GAP
  
• Single-molecule imaging analysis of Ras activation in living cells
  
• small GTPases-Ras
  
• Sprouty1 and Sprouty2 provide a control mechanism for the Ras-MAPK signalling pathway
  
• Stressing Rac, Ras, and Downstream Heat Shock Protein 70
  
• Structural Evidence For Feedback Activation By Ras·gtp Of The Ras-Specific Nucleotide Exchange Factor Sos
  
• Super Ras
  
• Targeting the Ras signaling pathway
  
• TGF-B and Ras-MAPK in TGFb signaling
  
• The many faces of Ras-recognition of small GTP-binding proteins
  
• The polybasic region of Ras and Rho family small GTPases
  
• The Ras Binary Switch-An Ideal Processor For Decoding Complex Ca2+ Signals
  
• The Ras-MAPK cascade and the control of positive selection
  
• The Ras-Raf relationship
  
• the regulation of the Ras-Raf-MEK-ERK pathway by protein interactions
  
• The role of phosphatidic acid in the regulation of the Ras-MEK-Erk signaling cascade
  
• The role of protein tyrosine phosphatase 1B in Ras signaling
  
• The structural basis for the transition from Ras-GTP to Ras-GDP
  
• Translational Control of the Antiapoptotic Function of Ras
  

  心血管系统

• Activation of the Small GTP-binding Protein Ras in the Heart by Hypertrophic Agonists
  
• Aldosterone Stimulates Proliferation Of Cardiac Fibroblasts By Activating Ki-Rasa And Mapk1-2 Signaling
  
• Angiotensin II Stimulates Platelet-Derived Growth Factor-B Chain Expression in Newborn Rat Vascular Smooth Muscle Cells and Neointimal Cells Through 1-1-Ras, Extracellular Signal–Regulated Protein Kinase
  
• Angiotensin II–Induced Hypertension-Contribution of Ras GTPase-Mitogen-Activated Protein Kinase and Cytochrome P450 Metabolites
  
• Blockade Of The Ras Increases Adiponectin Concentrations In Hypertension
  
• Cell Type–Specific Angiotensin II–Evoked Signal Transduction Pathways
  
• Contribution of Ras GTPase-MAP Kinase and Cytochrome P450 Metabolites to Deoxycorticosterone-Salt–Induced Hypertension
  
• dependent ERK Activation by the Human Gs-coupled Serotonin
  
• Expression of c-myc and H-ras and Absence of Expression of p53 and bcl-2 Genes in Atherosclerotic
  
• Functional Inhibition of Ras by S-trans,trans-Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis
  
• Galectin-3 Expression In Macrophages Is Signaled By Ras-Map Kinase Pathway And Up-Regulated By Lipoproteins
  
• Growth Inhibitory Signalling By Tgfβ Is Blocked In Ras-Transformed Intestinal Epithelial Cells
  
• HDL-induced Signaling of the MAPK Pathway Involves Scavenger Receptor-Activation of Ras
  
• High Density Lipoprotein–Induced Angiogenesis Requires the Activation of Ras-MAP Kinase in Human Coronary Artery Endothelial Cells
  
• Hydroxymethylglutaryl Coenzyme A Reductase Inhibitor Simvastatin Prevents Cardiac Hypertrophy Induced by Pressure Overload and Inhibits p21ras Activation
  
• Interactions between the renin-angiotensin system and dyslipidemia
  
• Interleukin-1β Regulation of the Human Brain Natriuretic Peptide Promoter Involves Ras-, Rac-, and p38 Kinase–Dependent Pathways in Cardiac Myocytes
  
• LDL-Activated p38 in Endothelial Cells Is Mediated by Ras
  
• Lipoprotein Promotes Caveolin-1 and Ras Translocation to Caveolae
  
• Myocardial Infarction-Gene-Gene Interaction in the RAS System in the Predisposition to Myocardial Infarction
  
• Oxidized Phospholipid-Induced Endothelial Cell-Monocyte Interaction Is Mediated by a cAMP-Dependent R-Ras
  
• Polymorphisms in the RAS and cardiac function
  
• Protection of Human Endothelial Cells From Oxidative Stress-Role of Ras-ERK1-2 Signaling
  
• Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload
  
• Rapid Activation of Ras by Fluid Flow Is Mediated by Gq and Gβ Subunits of Heterotrimeric G Proteins in Human Endothelial Cells
  
• RAS and connective tissue in the heart
  
• Ras Induces Vascular Smooth Muscle Cell Senescence And Inflammation In Human Atherosclerosis
  
• Ras Mediates Redox-sensitive Signaling by Angiotensin II in Vascular Smooth Muscle Cells
  
• Ras Protein Contributes to Cerebral Vasospasm in a Canine Double-Hemorrhage Model
  
• Ras Reduces L-Type Calcium Channel Current in Cardiac Myocytes
  
• Ras, Akt, and Mechanotransduction in the Cardiac Myocyte
  
• Ras-Erk Signaling Is Essential for Activation of Protein Synthesis by Gq Protein-Coupled Receptor Agonists in Adult Cardiomyocytes
  
• Ras-Rac-Dependent Activation of p38 Mitogen-Activated Protein Kinases in Smooth Muscle Cells Stimulated by Cyclic Strain Stress
  
• Regulation of vascular smooth muscle cell growth-targeting the final common pathway
  
• Role of Calcium-Sensitive Tyrosine Kinase Pyk2-CAKβ-RAFTK in Angiotensin II–Induced Ras-ERK Signaling
  
• Sarcoplasmic reticulum calcium defect in Ras-induced hypertrophic cardiomyopathy heart
  
• Shear Stress Activates p60src-Ras-MAPK Signaling Pathways in Vascular Endothelial Cells
  
• Short-Term Local Delivery of an Inhibitor of Ras Farnesyltransferase Prevents Neointima Formation In Vivo After Porcine Coronary Balloon Angioplasty
  
• Statins and Blockers of the Renin-Angiotensin System_Vascular Protection Beyond Their Primary Mode of Action
  
• Stimulation of angiogenesis by Ras proteins
  
• The renin–angiotensin system and experimental heart failure
  
• The Third Cytoplasmic Loop of the Angiotensin II Type 1 Receptor Exerts Differential Effects on Extracellular Signal–Regulated Kinase and Apoptosis via Ras-and Rap1-Dependent Pathways
  
• Vascular inflammation and the renin-angiotensin system
  
• Vegf-A And Vβ3 Integrin Synergistically Rescue Angiogenesis Via N-Ras And Pi3-K Signaling In Endothelial Cells
  

  肿瘤

• A Conditionally Replicating Adenovirus Targeted To Tumor Cells Through Activated Ras-Mapk-Selective Mrna
  
• An Inducible Melanoma Model Implicates a Role for RAS in Tumor
  
• Blocking Oncogenic Ras Signaling for Cancer Therapy
  
• Epigenetic Inactivation Of The Ras-Association Domain Family 1 (Rassf1a) Gene In Carcinogenesis
  
• Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin
  
• molecular medicine-RAS inhibitors-potential for cancer therapeutics
  
• NF-B blockade and oncogenic Ras trigger invasive human epidermal neoplasia
  
• Nuclear Ras_Unexpected Subcellular Distribution of Oncogenic Forms
  
• Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer
  
• Pro-apoptotic Ras Effector Nore1 May Serve as a Ras-regulated Tumor Suppressor in the Lung
  
• Ras as a target in cancer therapy
  
• Ras family genes-an interesting link between cell cycle and cancer.
  
• Ras interference as cancer therapy
  
• Ras superfamily monomeric G proteins in carcinoma cell motility
  
• Regulation of angiogenesis and tumorigenesis-Oncogenic Ras and its role in tumor cell invasion and metastasis
  
• Role of Telomerase in Cell Senescence and Oncogenesis
  
• Targeting RAS signalling pathways in cancer therapy
  
• The Ras family of GTPases in cancer cell invasion
  

  ras抑制因子

• A novel Ras inhibitor, Eri1
  
• ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits breast cancers
  
• Esculetin inhibits Ras-mediated cell proliferation
  
• Evidence for proteasome dysfunction in cytotoxicity mediated by anti-Ras intracellular antibodies
  
• Inhibition of H-ras as a treatment for experimental brain C6 glioma
  
• Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras
  
• Kos1, a nonreceptor tyrosine kinase that suppresses Ras signaling
  
• Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras
  
• Sef is a spatial regulator for Ras-MAP kinase signaling
  
• Sprouty1 and Sprouty2 provide a control mechanism for the Ras-MAPK signalling pathway
  
• SPRY2 Is an Inhibitor of the Ras_Extracellular Signal-Regulated Kinase Pathway in Melanocytes and Melanoma Cells with Wild-Type BRAF but Not with the V599E Mutant
  
• Synthesis and Evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of Ras-MAPK signaling c
  
• The inhibition of Ras farnesylation leads to an increase in p27Kip1 and G1 cell cycle arrest
  
• The ras-binding domain of ral GDS-like protein-2 as a ras inhibitor in smooth muscle cells
  
• Differences on the Inhibitory Specificities of H-Ras, K-Ras, and N-Ras
  
• Prospects for anti-ras drugs
  
• Raf signalling and emerging pharmacotherapeutic targets
  
• Ras inhibitors and anti-cancer drugs
  
• RAS inhibitorsRAS inhibitors-potential for cancer therapeutics potential for cancer therapeutics
  
• Somatostatin Receptor Inhibits Cell Proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2
  
• Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor
  
• Suppression of Ras-stimulated transformation by the JNK signal transduction pathway
  
• Targeting Ras signaling through inhibition of carboxyl methylation
  
• Treatment Of Metastatic Melanoma With An Orally Available Inhibitor Of The Ras-Raf-Mapk Cascade
  

  其它

• human cognitive disorders and the ras-ERK-CREB pathway
  
• Inhibition of Intimal Thickening in the Rat Carotid Artery Injury Model by a Nontoxic Ras Inhibitor
  
• Inhibitors of RAS signal transduction as antitumor agents
  
• new targets-From Ras signalling to ChoK inhibitors
  
• Positive and negative regulators of Ras in T cells
  
• Ras and Seppuku in Neuroblastoma
  
• Ras and TGF cooperatively regulate epithelial cell plasticity and metastasis