生物化學(xué)：第20章 癌基因、抑癌基因

第第 二二 十十 章章 癌基因、抑癌基因癌基因、抑癌基因與生長因子與生長因子 Oncogenes, Tumor suppressor gene and Growth Factors目目 錄錄癌基因、抑癌基因與生長因子的關(guān)系癌基因、抑癌基因與生長因子的關(guān)系癌基因癌基因抑癌基因抑癌基因生長因子生長因子正調(diào)控正調(diào)控負(fù)調(diào)控負(fù)調(diào)控產(chǎn)物產(chǎn)物第第 一一 節(jié)節(jié) 癌癌 基基 因因Oncogenes癌基因癌基因(oncogene)細(xì)胞內(nèi)控制細(xì)胞生長和分化的基因，它細(xì)胞內(nèi)控制細(xì)胞生長和分化的基因，它的結(jié)構(gòu)異?；虮磉_異常，可以引起細(xì)胞癌變。的結(jié)構(gòu)異?；虮磉_異常，可以引起細(xì)胞癌變。Definitions Oncogenes are the genes that are capable of are the genes that are capable of transforming a normal cell into a cancerous cell, leading transforming a normal cell into a cancerous cell, leading to a change of the hereditary character of their coding to a change of the hereditary character of their coding region or regulating area under certain condition. region or regulating area under certain condition. Oncogenes can be divided into two kinds:Oncogenes are also seen in oncogenic viruses. (Viraloncogenes are derived from normal host genes that have become incorporated into the viral genome and subsequently undergo mutation.)Oncogenes result from the mutation of normal genes (proto-oncogenes or cellular oncogene).病毒癌基因病毒癌基因(virus oncogene,v-onc)存在于病毒基因組中的癌基因，它不編存在于病毒基因組中的癌基因，它不編碼病毒的結(jié)構(gòu)成分，對病毒復(fù)制也沒有作用，碼病毒的結(jié)構(gòu)成分，對病毒復(fù)制也沒有作用，但可以使細(xì)胞持續(xù)增殖。但可以使細(xì)胞持續(xù)增殖。一、病毒癌基因一、病毒癌基因 LTR gag pol env src LTR癌基因癌基因酪氨酸酪氨酸 激酶激酶* *病毒基因組結(jié)構(gòu)病毒基因組結(jié)構(gòu)目目 錄錄二、細(xì)胞癌基因二、細(xì)胞癌基因v細(xì)胞癌基因細(xì)胞癌基因(cellular-oncogene, c-onc)存在于生物正常細(xì)胞基因組中的癌基因，或存在于生物正常細(xì)胞基因組中的癌基因，或稱稱原癌基因原癌基因 (proto-oncogenes , pro-onc) 。Proto-oncogenes OncogenevProto-oncogene: normal cell gene, involved in the control of normal cell growth and proliferation (cell cycle control, transcription factor, DNA repair gene)voncogene: mutated/de-regulated proto-oncogene gene whose inappropriate expression leads to cancer細(xì)胞癌基因的特點細(xì)胞癌基因的特點廣泛存在于生物界中；廣泛存在于生物界中；基因序列高度保守；基因序列高度保守；作用通過其產(chǎn)物蛋白質(zhì)來體現(xiàn)；作用通過其產(chǎn)物蛋白質(zhì)來體現(xiàn)；被激活后，形成癌性的細(xì)胞轉(zhuǎn)化基因。被激活后，形成癌性的細(xì)胞轉(zhuǎn)化基因。細(xì)胞癌基因的分類及其產(chǎn)物細(xì)胞癌基因的分類及其產(chǎn)物根據(jù)原癌基因的表達產(chǎn)物在細(xì)胞中的定位根據(jù)原癌基因的表達產(chǎn)物在細(xì)胞中的定位和功能分為：和功能分為：1. src家族家族 酪氨酸蛋白激酶酪氨酸蛋白激酶2. ras家族家族 P213. myc家族家族 核內(nèi)核內(nèi)DNA結(jié)合蛋白結(jié)合蛋白4. sis家族家族 P28(類人血小板源生長因子類人血小板源生長因子)5. myb家族家族 核內(nèi)轉(zhuǎn)錄因子核內(nèi)轉(zhuǎn)錄因子目目 錄錄（一）獲得啟動子與增強子（一）獲得啟動子與增強子 proto-oncogene proto-oncogene obtaining promotor and enhancerobtaining promotor and enhancer（二）基因易位（二）基因易位 gene translocationgene translocation（三）原癌基因擴增（三）原癌基因擴增 Gene amplificationGene amplification（四）點突變（四）點突變 mutationmutation出現(xiàn)新的表達產(chǎn)物出現(xiàn)新的表達產(chǎn)物 出現(xiàn)過量的正常表達產(chǎn)物出現(xiàn)過量的正常表達產(chǎn)物出現(xiàn)異常、截短的表達產(chǎn)物出現(xiàn)異常、截短的表達產(chǎn)物三、癌基因活化的機制三、癌基因活化的機制癌基因被激活的結(jié)果癌基因被激活的結(jié)果（一）細(xì)胞外生長因子（一）細(xì)胞外生長因子 sis-P28（二）跨膜的生長因子受體（二）跨膜的生長因子受體c-src、c-abl、c-mos 、c-raf（三）細(xì)胞內(nèi)信號傳導(dǎo)體（三）細(xì)胞內(nèi)信號傳導(dǎo)體c-src、c-abl、c-ras、c-mas、H-ras、K-ras、N-ras、crk（四）核內(nèi)轉(zhuǎn)錄因子（四）核內(nèi)轉(zhuǎn)錄因子 myc、fos四、原癌基因的產(chǎn)物與功能四、原癌基因的產(chǎn)物與功能目目 錄錄 It may be helpful to think of a cell as a car. For it to work properly, there need to be ways to control how fast it goes. A proto-oncogene normally functions in a way that is similar to a gas pedal - it helps the cell grow and divide. An oncogene could be compared to a gas pedal that is stuck down, which causes the cell to divide out of control. 第第 二二 節(jié)節(jié)抑抑 癌癌 基基 因因Anti-oncogenes抑癌基因抑癌基因(cancer suppressive gene, anti-oncegene)抑制細(xì)胞過度生長、增殖從而遏制腫瘤形抑制細(xì)胞過度生長、增殖從而遏制腫瘤形成的基因。成的基因。一、抑癌基因的基本概念一、抑癌基因的基本概念Tumor Suppressor Genes Tumor suppressor genes are cellular genes that normally suppress cell growth and proliferation. Tumor Suppressor Genes f u n c t i o n t o p r e v e n t m a l i g n a n t transformation, Usually act in a recessive fashion. 細(xì)胞雜交試驗細(xì)胞雜交試驗正常細(xì)胞正常細(xì)胞腫瘤細(xì)胞腫瘤細(xì)胞非腫瘤型雜交細(xì)胞非腫瘤型雜交細(xì)胞雜交融合雜交融合腫瘤細(xì)胞腫瘤細(xì)胞1 1腫瘤細(xì)胞腫瘤細(xì)胞2 2雜交融合雜交融合非腫瘤型雜交細(xì)胞非腫瘤型雜交細(xì)胞正常細(xì)胞正常細(xì)胞失去某些基因失去某些基因腫瘤細(xì)胞腫瘤細(xì)胞二、常見的抑癌基因二、常見的抑癌基因（一）視網(wǎng)膜母細(xì)胞瘤基因（一）視網(wǎng)膜母細(xì)胞瘤基因（Rb基因）基因）G0 G1期期Rb蛋白蛋白E-2FS期期E-2FDNAmRNADNA三、抑癌基因的作用機制三、抑癌基因的作用機制Rb蛋白蛋白（二）（二）P53蛋白蛋白基因衛(wèi)士基因衛(wèi)士P53蛋白蛋白解鏈酶解鏈酶復(fù)制因子復(fù)制因子A AP21蛋白蛋白細(xì)胞停滯于細(xì)胞停滯于G G1 1期期細(xì)胞自殺細(xì)胞自殺酸性區(qū)核心區(qū)堿性區(qū)P53蛋白蛋白 DNA損傷損傷P21基因基因P53蛋白蛋白抑抑 制制P53蛋白蛋白成功修復(fù)成功修復(fù)修復(fù)失敗修復(fù)失敗 A tumor suppressor gene is like the brake pedal on a car it normally keeps the cell from dividing too quickly just as a brake keeps a car from going too fast. When something goes wrong with the gene, such as a mutation, cell division can get out of control. An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off). 第第 三三 節(jié)節(jié)生生 長長 因因 子子Growth factors生長因子生長因子(growth factor) 通過質(zhì)膜上特異的受體，將信息傳遞至通過質(zhì)膜上特異的受體，將信息傳遞至細(xì)胞內(nèi)部，調(diào)節(jié)細(xì)胞生長與增殖的多肽類物質(zhì)。細(xì)胞內(nèi)部，調(diào)節(jié)細(xì)胞生長與增殖的多肽類物質(zhì)。一、概述一、概述Growth factorsvDefinition protein or peptide that secreted by cells play the function of signal transmitting between the cells and promote cell proliferation and differentiation, be called cell factor or cytokine also. 作用模式作用模式 內(nèi)分泌內(nèi)分泌 (endocrine)旁分泌旁分泌 (paracrine)自分泌自分泌 (autocrine)vExert its function by three ways Endocrine Paracrine autocrine The same growth factor acts on different cells and bring different functions,the same cell can be affected by regulation of different growth factors. serum contains many kinds of growth factors.產(chǎn)生相應(yīng)第二信使產(chǎn)生相應(yīng)第二信使胞內(nèi)相關(guān)蛋白胞內(nèi)相關(guān)蛋白質(zhì)被磷酸化質(zhì)被磷酸化與與膜受體膜受體結(jié)合結(jié)合酪氨酸激酶活化酪氨酸激酶活化蛋白激酶活化蛋白激酶活化 核內(nèi)轉(zhuǎn)錄因子活化核內(nèi)轉(zhuǎn)錄因子活化基因轉(zhuǎn)錄基因轉(zhuǎn)錄與與胞內(nèi)受體胞內(nèi)受體結(jié)合結(jié)合生長因子生長因子 受受體復(fù)合物，活體復(fù)合物，活化相關(guān)基因化相關(guān)基因二、生長因子作用機制二、生長因子作用機制目目 錄錄在某些生理或病理條下，細(xì)胞接受到某種在某些生理或病理條下，細(xì)胞接受到某種 信號所觸發(fā)的并按一定程序緩慢死亡的過程。信號所觸發(fā)的并按一定程序緩慢死亡的過程。誘導(dǎo)因素：誘導(dǎo)因素：野生型野生型p53基因基因抑制因素：抑制因素：突變型突變型p53基因基因 神經(jīng)生長因子神經(jīng)生長因子(NGF)三、生長因子與疾病三、生長因子與疾病（一）細(xì)胞凋亡（一）細(xì)胞凋亡細(xì)胞凋亡細(xì)胞凋亡 (apoptosis)1. 原發(fā)性高血壓原發(fā)性高血壓myc、fos的激活促平滑肌細(xì)胞增生的激活促平滑肌細(xì)胞增生p53低表達或突變低表達或突變2. 動脈粥樣硬化動脈粥樣硬化PDGF過量產(chǎn)生過量產(chǎn)生3. 心肌肥厚心肌肥厚ras、myb、myc、fos等過量表達等過量表達IGF、TGF、FGF（二）心血管疾?。ǘ┬难芗膊?