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1、第二十章chapter 20,癌基因、抑癌基因与生长因子Oncogenes,Anti-oncogenes and Growth Factors,癌基因、抑癌基因与生长因子的关系,oncogenes,anti-oncogenes,cells,growth factors,up-regulation,down-regulation,product,癌基因（oncogene）病毒癌基因（virus oncogene,v-onc）细胞癌基因（cellular oncogene,C-onc）原癌基因（proto-oncogene）,Oncogenes are genes which control th
2、e growth and differentiation of cells(控制细胞生长和分化),the abnormality of their structure or expression(结构异常或表达异常)can cause cancer(引起细胞癌变).,原癌基因(proto-oncogenes，pro-onc),If Oncogenes present in the normal cellular genome,they are named as proto-oncogenes or cellular oncogenes.存在于生物正常细胞基因组中的癌基因。,癌基因(oncoge
3、ne),癌基因Oncogenes,第一节,存在于病毒基因组中的癌基因，它不编码病毒的结构成分，对病毒复制也没有作用，但可以使细胞持续增殖。Virus oncogenes are oncogenes in the viral genome，although they dont encode the structural proteins of the viruses and dont play roles in the viral replication,but they can promote cell proliferation continuously.,一、病毒癌基因,病毒癌基因(vir
4、us oncogene,v-onc),*the structure of viral genome,Viral oncogene comes from cellular oncogene.,广泛存在于生物界 Present in biological kingdom extensively基因序列高度保守 The sequence are conservative highly维持正常生理功能、调控细胞生长和分化起重要作用 Play vital roles in normal control of cell life 被激活后，导致正常细胞癌变 Cause cells to become ca
5、ncerous when oncogenes are activated,二、细胞癌基因(Cellular oncogenes),Classification and product of the cellular oncogenes,Src family：protein-tyrosine kinase Ras family：p21，a kind of small G-protein Myc family：DNA binding proteinSis family：p28(truncated PDGF),growth factorMyb family：nuclear transcription
6、al factor,Functional classes of oncogenes,Classification of the expressed products,Oncogenes,Properties of theexpressed products,Growth factors sis PDGF-chain growth factor Int-2 growth factorReceptor protein erb-B truncated EGF receptor tyrosine kinase ros,neu ligands are not knownNon-receptor src,
7、yes membrane associated tyrosine kinase protein kinases fps tyrosine kinases not associated with membrane raf,mos serine-threonine protein kinasesG proteins H-ras,K-ras,N-ras membrane associated small G proteinsTranscription factors myc,fos,jun regulators of proliferation erb A,ski regulators of dif
8、ferentiationCell cycle regulators PRAD 1 cyclin related factors,Extracellular growth factors（生长因子）：sisTrans-membrane growth factors receptors（生长因子受体）:c-src、c-abl、c-mos、c-rafIntracellular signal factors（细胞内信号分子）:c-src、c-abl、c-ras、c-mas、ras、crkNuclear transcription factors（核转录因子）：myc、fos,三、原癌基因的产物与功能,
9、（1）获得启动子与增强子 obtain promoter and enhancer,四、癌基因活化的机制mechanism of oncogene activation,Such as insertion of pre-virus which cantains stronger promoter and enhancer in LTR.,（2）染色体易位(Chromosomal translocation),during chromosomal translocation,the translocation and the rearrangement of certain genes occu
10、rred,so that no activity of the original proto-oncogene moved to a strong promoter or enhancer was activated and expressed,leading to tumor occurred,The chromosomal translocation characteristic of Burkitt lymphoma,Translocation of oncogenes,（三）原癌基因扩增 Proto-oncogenes amplification,原癌基因拷贝数量的增加.,The re
11、lationship of the N-myc oncogene and Rb gene,（四）点突变（Point mutation in coding region）,The components of the H-ras-1 oncogene,Loss of chromosomal material and deletion of regulatory sequencesInsertion of pre-virusesDemethylation of DNACo-operation between oncogenes,出现新的表达产物appears the new product出现过量的
12、正常表达产物appears the excessive normal product出现异常、截短的表达产物appears the abnormal or truncated product,癌基因激活的结果：,抑癌基因Anti-oncogenes,第二节,抑癌基因(cancer suppressive gene,anti-oncegene),一、抑癌基因的基本概念,They are genes which can Inhibit the growth of normal cells and restrain the rate of division of normal cells.,抑制细胞
13、生长和增殖的基因。,细胞杂交试验（Cellular hybridization experiments）,normal cellscancerous cells,noncancerous hybrid cells,cancerous cells 1cancerous cells 2,noncancerous hybrid cells,hybridization,二、常见的抑癌基因,（一）视网膜母细胞瘤基因（Rb基因）,G0 G1期,S期,E-2F,DNA,mRNA,DNA,三、抑癌基因的作用机制,（二）P53,P53蛋白,解链酶,复制因子A,P21蛋白,细胞停滞于G1期,细胞调亡,DNA损伤,
14、P53蛋白,P53蛋白,生长因子Growth factors,第三节,生长因子(growth factor),一、概述,通过质膜上特异的受体，将信息传递至细胞内部，调节细胞生长与增殖的多肽类物质。,Growth factors They are polypeptide substance which can transmit a message to the interior of the cells by the specific receptors on the plasma membrane,in this way they can regulate the growth and pro
15、liferation of the cells.,Y,Y,Y,blood vessel,Signaling substance,Y,receptor,target cell,target cell,secretive cell,Y,作用模式：,内分泌(endocrine)旁分泌(paracrine)自分泌(autocrine),How the growth factors act?,produce the secondary message,phosphorylate the associate proteins in cell,bind to the membrane receptors,a
16、ctivate protein-tyrosine kinase,activate the protein kinase,activate the nucleartranscription factors,gene transcription,bind to the nuclear receptors,growth factor-receptor complex,activate the associate gene.,产生相应第二信使,胞内相关蛋白质被磷酸化,与膜受体结合,酪氨酸激酶活化,蛋白激酶活化,核内转录因子活化,基因转录,与胞内受体结合,生长因子-受体复合物，活化相关基因,二、生长因子
17、作用机制,在某些生理或病理条下，细胞接受到某种 信号所触发的并按一定程序缓慢死亡的过程。,诱导因素：野生型p53基因抑制因素：突变型p53基因、神经生长因子(NGF),（一）细胞凋亡(apoptosis),The relationship of oncogenes、anti-oncogenes、growth factors and diseases,myc、fos的激活促平滑肌细胞增生；p53低表达或突变。,2.动脉粥样硬化：PDGF过量产生,ras、myb、myc、fos等过量表达，有关的生长因子有IGF、TGF、FGF。,（二）心血管疾病,3.心肌肥厚：,1.原发性高血压：,肿瘤细胞特征之一：增殖失控,生长信号自给自足。生长抑制信号失敏。复制能力失控。,p53基因突变PTEN基因突变Fas信号减弱，FasL表达上调：凋亡淋巴细胞逃避免疫反应。病毒抗凋亡蛋白抑制宿主细胞凋亡：p35BcL-2同源HBX结合p53E6促进p53分解,肿瘤细胞特征之二：逃避凋亡,肿瘤细胞特征之三：侵袭和转移,包括六个步骤：原发肿瘤细胞穿透组织基底膜；穿破血管或淋巴管壁进入血液循环；停留于靶器官淋巴管和毛细血管壁内皮细胞上；穿出血管侵入周围组织；继续生长、增殖；新生血管长入形成转移瘤；,肿瘤扩散的分子基础,肿瘤血管生成和转移,
