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1、Gene and DiseaseYuan Ping OncogeneTumor Suppressor Genes Growth FactorsYUAN PINGCHAPTER 21Cancer cells are characterized by:lDiminished or unrestrained control of growth;lInvasion of local tissues;lSpread,or metastasis,to other parts of the body.Growth out of controlCell division without permission
2、Growth out of controlImmortality Telomerase is active in many cancer cells.Growth out of controlRefuse suicide(against apoptosis)Cell damageapoptosisIgnore growth inhibition Cells grows only to a limited density,because growth is inhibited perhaps by processes involving cell-cell contact.Spread,or m
3、etastasis,to other parts of the bodylMetastasis is the most dangerous property of tumor cells.Angiogenesis Carcinogeneic agents(Carcinogens)lPhysical agents:UV,x-ray,-raylChemical agents:benzene,asbestos,aflatoxin,lBiological agents:some DNA and RNA viruseslPersonal factors:immunity,inherited charac
4、teristicDNAOncogenes Tumor suppressor genesPositiveregulation Accumulation of genetic defectscancerNegative regulation Section I OncogeneslOncogenes are intracellular genes that control cell growth and differentiation,the abnormity of structure or expression of oncogenes causes cancer.lOncogenes wer
5、e initially identified as genes carried by viruses that cause transformation of their target cells.lThe oncogenes found in the cellular DNA,are called proto-oncogenes,pro-onc.Two types of oncogenes:lViral oncogenes(v-onc)lCellular oncogenes(c-onc)Viral oncogenes(v-onc)lTumor viruses:DNA viruses,RNA
6、viruseslViral oncogenes are the genes existed in tumor viruses(specially in retroviruses)and make target cells transformed.RSV(avian Rous sarcoma virus)LTRLTRgagpolenvsrcLong terminal repeatRegulate and initiate transcriptionVirus core proteinReverse transcriptaseIntegraseEnvelopeTyrosine kinaseSrc
7、is not the structural or functional proteins of the virus,and does not regulate the life cycle of the virusRNA virusRNADNAProvirus c-oncReverse transcriptaseintegraseRetrovirusus cause tumors in two general ways:i.The virus itself carry a gene whose product alters the control of cell proliferation.o
8、ncogeneLTRLTRIntergrated RetrovirusThe strong viral PromoterPThese v-onc tend to produce tumor cells at high frequency.ii.Viral integration can occur near or within an important control gene in the host chromosome,raising the level of expression of that gene.c-oncLTRLTRIntergrated RetrovirusPPThe pr
9、obability of this happening is generally low because viral integration is not specifically target to particular sites.Cellular oncogenes(c-onc)lc-onc are necessary for the cell.lc-onc control cell growth and differentiation.lAlteration of structure or expression of oncogenes are tumorigenic.Characte
10、ristics of c-onclWildly distributed in the biology;lHighly conserved in gene sequence;lGene products(proteins)are necessary for maintaining normal cellular functions,regulation cell growth and differentiation;lActivation of c-one will cause malignant transformation.Products of c-onelGrowth factorslR
11、eceptors of growth factorslIntracellular signal transductors:non-RTK,serine/threonine kinase,ras,phospholipase,et al.lNuclear transcription factorsOncogenes 1.src:tyrosine kinase2.ras:signal tranductors3.myc:DNA bound proteins,regulate gene expression4.sis:growth factor,stimulate cell proliferation5
12、.myb:nuclear transcription factorsMyc-activated mechanism of action具有酪氨酸蛋白激酶活性的具有酪氨酸蛋白激酶活性的src癌基因家族及其表达产物癌基因家族及其表达产物 原癌基因原癌基因 病毒癌基因病毒癌基因癌基因癌基因 蛋白产物蛋白产物 细胞定位细胞定位 癌基因癌基因 蛋白产物蛋白产物 细胞定位细胞定位C-src pp60c-src 细胞浆细胞浆 V-src pp60v-src 膜膜/细胞支架细胞支架C-abl pl50c-abl 细胞浆细胞浆 V-abl p160gag-abl 膜膜C-yes pp62c-yes /V-yes
13、 p90geg-src 膜膜C-fps p98c-fps 可溶组分可溶组分 V-fps p140geg-fps 膜膜/可溶可溶C-fes p92c-fes /V-fes p85geg-fes 胞浆胞浆C-fgr /V-fgr p70geg-fgr 胞浆胞浆C-ros /V-ros p68geg-ros 膜膜C-kit /V-kit p80geg-kit /C-erb-B EGF受体受体 浆膜浆膜 V-erb-B gq68/74v-erb-B 膜膜C-erb-B-2 /浆膜浆膜 gp180 膜膜 PDGF受体受体 浆膜浆膜C-fms csf-1受体受体 浆膜浆膜 V-fms gp165v-fms
14、 膜膜C-fms 胰岛素受体胰岛素受体 浆膜浆膜C-fms IGF-1受体受体 浆膜浆膜C-fms p56I stra 浆膜浆膜C-fms P75 胞浆胞浆met 膜膜raslRas genes were discovered in murine sarcoma viruses,which were highly related cellular sequences of cellular origin that were called ras for rat sarcoma(Barbacid,1987).lAn alterred version is found in 30%to 40%of
15、 all human tumors.lMembranes of the ras gene family,which are found normally in a variety of eukaryotic organisms ranging from yeasts to humans,act as signalling proteins that stimulate many pathways associated with cell proliferation.编码编码的蛋白的蛋白质质原癌基因原癌基因激活机制激活机制相关人相关人类肿类肿瘤瘤生生长长因子：因子：PDGF链链sis过过度表达度
16、表达星形星形细细胞瘤，骨肉瘤胞瘤，骨肉瘤FGFhst-1,int-2过过度表达度表达胃癌，膀胱癌，乳腺癌胃癌，膀胱癌，乳腺癌生生长长因子受体：因子受体：EGF受体受体erb-B1扩扩增增胶胶质质瘤瘤EGF样样受体受体 neu(erb-B2)扩扩增增乳腺癌，卵巢癌，乳腺癌，卵巢癌，肾肾癌癌信号信号转导转导蛋白：蛋白：GTP结结合蛋白合蛋白ras点突点突变变 多种人体多种人体肿肿瘤，包括肺，瘤，包括肺，结肠结肠，胰，白血病胰，白血病酪氨酸激酪氨酸激酶酶abl易位易位慢性粒慢性粒细细胞性，急性淋巴胞性，急性淋巴细细胞胞性白血病性白血病核核调节调节蛋白：蛋白：转录转录激活蛋白激活蛋白myc易位易位伯基
17、特淋巴瘤伯基特淋巴瘤Nmyc扩扩增增神神经经母母细细胞瘤，小胞瘤，小细细胞肺癌胞肺癌线线粒体蛋白：粒体蛋白：bcl-2易位易位滤滤泡性泡性B细细胞淋巴瘤胞淋巴瘤General comments on activation of oncogeneslPoint mutation in coding regionltranslocationlGene amplificationlLoss of chromosomal material and deletion of regulatory sequenceslInsertion of pre-viruseslMethylation of DNAlC
18、o-operation between oncogenesNew productsOver expressionAbnormal or truncated productsActivation of protein kinase by chromosome rearrangementkinaseBcrChromosome 9Chromosome 22Breakage and rejoiningkinaseBcrTUMOR SUPPRESSOR GENESlTumor suppressor genes:genes whose products are needed for normal cell
19、 function,and whose loss of function causes tumors.Tumor suppressor genelTumor suppressor genes were discovered in a childhood form of cancer called retinoblastoma.This is a malignant tumor of retinal neuroblast,which are precursor cells of photoreceptor cells in the retina.RBlRetinoblastoma is caus
20、ed by loss of both copies of the RB gene in chromosome.RB+RB+Normal individual has 2 RB+alleles.RB+RB-Loss of one allele in somatic cells has no effect;lose of one allele in germ cells creates carrier with wild phenotype.RB-RB-Loss of both alleles induces tumor cells formation.lRB is a nuclear phosp
21、hoprotein that influences the cell cycle,whose phosphorylation status is apparently important with respect to its function.RBEF2Cyclin-dependent KinasePO4RBPO4DNAReplication ProteinsDNA ReplicationEF2Control of DNA replication by Rb pathwayThe Rb gene acts as a gatekeeper in the transition from the
22、G1 to S phase in the cell cycle.Mutation or defect of the Rb gene,or RB protein lost the ability if binding EF2,allows the DNA synthesis to proceed.lThe main tumors in which inactivation of PB is an important factor include small cell lung cancers,adenocarcinomas of the prostate,and tumors originati
23、ng from retina,bone,and connective tissues.The P53 tumor suppressor gene acts as a guardian of the genomelMutations in P53 are the most common genetic alterations in human cancer,more than half of all human cancers either have lost p53 protein or have mutations in the gene.lP53 encodes a protein(des
24、ignated p53)of molecular mass 53 kDA.Activated transcriptionTBPMdm2E1Bp300/CBPSignalingDNA binding domainOligomerizesBinds to damaged DNASTRUCTURE OF p53Major effects of p53:lIt acts as a transcriptional activator,regulating certain genes involved in the cell cycle.lIt acts as a G1 checkpoint contro
25、l for DNA damage.lIt participates in the initiation of apoptosis.DNA damageActivation of p53In cells early in G1,p53 activates a checkpoint that prevent further progress until the damage has been repaired.Triggers apoptosisDamaged cell diesp53p53 in apoptosis:lActivate key genes involved in apoptosi
26、s;lRepress genes necessary for cell surival;lBe a component of the biochemical series of events that result in apoptosis;Section IIIGrowth FactorGrowth factorlGrowth factors are polypeptides that regulate cells growth and proliferation.lFashions of growth factors:EndocrineParacrineAutocrineGrowth Fa
27、ctor&DiseasesTumorslActivation of oncogeneslInactivation of tumor suppressor geneslHypertensionlAtherosclerosislCardiac muscle Cardiovascular Diseases,CVDlYUAN PING room:13-08l Tel:62051350l e-mail:p53helicase复制因子复制因子Ap21蛋白蛋白G1-specific cell cycle arrest DNA damageP21基因基因p53_p53Successfully repairApoptosis Fail to repair