1、Subcellular distribution of v 6图1 卵巢肿瘤A：GAe组雏鸡接种MDV GA株后40天，卵巢形成明显肿瘤（如箭头所示）；B：GA0组卵巢正常（如箭头所示）；C：异常卵巢和正常卵巢的直观比较）图2 睾丸肿瘤A：GA0组睾丸正常（如箭头所示）；B：GAe组雏鸡接种MDV GA株后40天，睾丸形成明显肿瘤（如箭头所示）；C：异常睾丸和正常睾丸的直观比较）l对肿瘤发生的分子机制，最初人们认为是对肿瘤发生的分子机制，最初人们认为是病毒瘤基因病毒瘤基因所致；所致；l7070年代中期，毕晓普和瓦慕斯发现动物正年代中期，毕晓普和瓦慕斯发现动物正常细胞中本来存在常细胞中本来存在癌
2、基因（原癌基因）癌基因（原癌基因）；l正常情况下，瘤基因对细胞的生长、分化、正常情况下，瘤基因对细胞的生长、分化、调节和维护正常功能起重要作用；调节和维护正常功能起重要作用；l近来发现细胞中有抑制肿瘤发生的近来发现细胞中有抑制肿瘤发生的抑瘤基抑瘤基因因。The vast majority of these mutations are somaticExampleOncogenes derived from growth factor receptors confer the ability to bypass the growth factor requirementleading to in
3、dependent growth.Act as a brake for cell division“GUARDIAN OF THE GENOME”PROBLEM:Mutation in tumour suppressor genes=brakes dont work,or there is an accumulations of mutations(DNA repair enzymes)The mutated gene product is not functional=NULL ALLELEInactivated tumour suppressor gene肿瘤发生肿瘤发生Activated
4、 proto-oncogene含转录含转录启动子启动子 LTR gag pol env src LTR 长末端长末端重复序列重复序列癌基因癌基因正常的病毒基因正常的病毒基因 产生病毒产生病毒表面糖蛋白表面糖蛋白产生逆转录产生逆转录酶和整合酶酶和整合酶 产生病毒产生病毒 垮膜蛋白垮膜蛋白产生产生p60p60srcsrc蛋白质，蛋白质，磷酸化蛋白。靶蛋磷酸化蛋白。靶蛋白磷酸化白磷酸化Rous于于1910年首先发现鸡肉瘤病毒（后称劳年首先发现鸡肉瘤病毒（后称劳斯肉瘤病毒斯肉瘤病毒RSV）基因扩增基因扩增蛋白质结构未变化，但总量大大提高蛋白质结构未变化，但总量大大提高基因扩增基因扩增 原癌基因原癌基因
5、基因在细胞中拷贝数增加，从而使可用的转基因在细胞中拷贝数增加，从而使可用的转录模板数大大增加。录模板数大大增加。染色体易位或重排染色体易位或重排慢性粒细胞白血症慢性粒细胞白血症(Chronic myeloid leukaemia，CML)is characterised bythe t(9;22)(q34;q11)reciprocal translocation病毒病毒启动子启动子插入插入基因间相互作用基因间相互作用 肿瘤细胞中常常不是由一种肿瘤细胞中常常不是由一种C-onc表达异常，表达异常，有时需几种有时需几种C-onc发生改变，产生协同作用方发生改变，产生协同作用方可奏效可奏效 正常细胞
6、的基因，具有相对稳定的甲基正常细胞的基因，具有相对稳定的甲基化类型，特别是原癌基因的甲基化可使其难化类型，特别是原癌基因的甲基化可使其难以表达。以表达。原癌基因甲基化水平降低原癌基因甲基化水平降低Examples of Oncogenes正常情况下抑癌基因的作用：正常情况下抑癌基因的作用：抑癌基因改变的分子基础抑癌基因改变的分子基础错配修复基因缺陷错配修复基因缺陷 守门基因和看护基因的突变失活守门基因和看护基因的突变失活 守门基因守门基因（gatekeeper gene）是指在细胞恶是指在细胞恶性转化过程中与癌基因启动相关的基因。性转化过程中与癌基因启动相关的基因。看护基因看护基因（caret
7、aker，gene）是指保持细胞是指保持细胞基因组稳定性，而与细胞恶性转化过程中癌基基因组稳定性，而与细胞恶性转化过程中癌基因的启动不直接相关的基因。因的启动不直接相关的基因。Examples of tumour suppressor genes includeRB1-retinoblastoma susceptibility gene WT1-Wilms tumour gene NF1-neurofibromatosis type 1 gene NF2-neurofibromatosis type 2 gene DCC-involved in colorectal cancer BRCA1,
8、BRCA2-involved in breast cancerToday we will look at these tumour suppressor genes:Rb()p53APC(腺瘤样结肠息肉腺瘤样结肠息肉)p53 functions as a molecular node in the DNA-damage response恶性肿瘤细胞在生物学研究中的应用恶性肿瘤细胞在生物学研究中的应用 无限制增长特性无限制增长特性 细胞分化幼稚细胞分化幼稚 细胞寿命长细胞寿命长 细胞的侵润性细胞的侵润性 致瘤性致瘤性 细胞的遗传性细胞的遗传性Clonal selection of cancer
9、cellsVariants over timeThe molecular mechanisms involved in classical cross-priming are illustrated.Dendritic cells(DCs)take up antigen by distinct endocytosis mechanisms and present it to CD4+T helper(TH)cells through MHC class II molecules and cross-present it to CD8+cytotoxic T lymphocytes(CTLs)t
10、hrough MHC class I molecules.Activated CD4+TH cells can stimulate CTLs through the production of interleukin-2(IL-2)and license DCs for cross-priming through CD40 ligand(CD40L)CD40 interactions.Licensed DCs upregulate expression of co-stimulatory molecules,such as CD70,CD80 and CD86,and downregulate
11、 inhibitory molecules,such as programmed cell death ligand(PDL1).Toll-like receptor(TLR)ligands further activate DCs and increase their cross-presentation activity.Cross-primed CTLs are programmed for survival and cease TNF-related apoptosis-inducing ligand(TRAIL)production.Helpless CTLs activated b
12、y unlicensed DCs die following secondary encounter with antigen in their effector phaseChemokine-mediated regulation of cross-priming is illustrated.CD4+TH cells,and the DCs they license,produce CC-chemokine ligand 3(CCL3),CCL4 and CCL5 in the presence of TLR ligands,which recruit naive CTLs for cla
13、ssical cross-priming.Alternatively,DCs licensed by natural killer T(NKT)cells produce the CC-chemokine receptor(CCR4)ligand CCL17,and NKT cells themselves produce the CCR4 ligand CCL22,which recruit naive CCR4+CTLs for cross-priming.The CCR4-and CCR5-mediated recruitment pathways are synergistic.In
14、this figure,dashed arrows indicate antigen routing for crosspresentation.-GalCer,-galactosylceramide;TCR,T cell receptor.Recruitment of cross-primed effector cytotoxic T lymphocytes into non-lymphoid tissues.Viral infection of tissue cells leads to their secretion of pro-inflammatory cytokines and i
15、nterferons that upregulate the expression of adhesion molecules,such as intercellular adhesion molecule 1(ICAM1),by endothelial cells.Effector cytotoxic T lymphocytes(CTLs)attach to these molecules and are nonspecifically recruited from the bloodstream into non-lymphoid tissues.In addition,recent st
16、udies have revealed two antigen-specific recruitment mechanisms:first,endothelial cells in certain tissues,such as the liver,pancreatic islets or the brain,can cross-present microbial antigen,which allows them to selectively recruit antigen-specific CTLs.Second,when specific CD4+T helper(TH)cells de
17、tect microbial(or self)antigen on non-cross-presenting tissue DCs,ligands for CC-chemokine receptor 5(CCR5)or CXC-chemokine receptor 3(CXCR3)are produced that recruit CTLs into the infected tissue.LFA1,lymphocyte function-associated antigen 1;TCR,T cell receptor.Growth factors(I)Growth factor recept
18、ors(II)Signal-transduction proteins(III)Transcription factors(IV)Pro-or anti-apoptotic proteins(V)Cell cycle control proteins(VI)DNA repair proteins(VII).Mutations in I-IV generally give rise to oncogenes.Class VI proteins act as tumour suppressors;mutations in these act recessively to release cells from control and surveillance,increasing the probability of cancer developing.7 proteins controlling cell growth
