如何回复SCI期刊给出的修改意见

1、CARCINOGENESIS:MOLECULAR BASIS OF CANCERDAVID LEWIN MD期刊杂志 http:/OVERVIEWnBASIC CONCEPTS OF ONCOGENES, TUMOR SUPPRESSOR GENES, APOPTOSIS, DNA REPAIR & TELOMERES nHOW THEY ARE ASSOCIATED WITH MALIGNANCYnPROPOSED FUNCTIONSnGENETIC ALTERATIONS ASSOCIATED WITH THEIR ACTIVATION OR LOSSFUNDAMENTAL PRI

2、NCIPLESnNon-Lethal genetic damage (Mutations)nAcquired Environment (next lecture)nInherited (Germ line)nTumors arise from a single progenitor cellnMonoclonal (X-linked isoenzyme)nTarget GenesnProto-oncogenes, TSG, Apoptosis, DNA repairnMultistep ProcessMONOCLONALITY:X-Linked IsoenzymePolyclonalMonoc

3、lonalKumar et al. Basic Pathology 6th ed. Fig. 6-15Simplified Cancer PathogenesisDamageGene ExpressionNormalMalignancyKumar et al. Basic Pathology 6th ed. Fig. 6-16ONCOGENESnPROTO-ONCOGENESnNORMAL CELLULAR GENEnALTERATIONS GIVE ONCOGENEnMUTATIONS, AMPLIFICATION, RETROVIRAL TRANSFERnDEFINE MOLECULAR

4、BASIS FOR CANCERnEXPLAIN MUTAGENS EFFECT ON CANCER DEVELOPMENTLABORATORY IDENTIFICATION OF ONCOGENESnACUTE RETROVIRAL TRANSDUCTION nACUTE TRANSFORMING VIRUSES n(V-ONC)nINSERTIONAL MUTAGENESISnSLOW TRANSFORMING VIRUSESnDNA TRANSFECTION (IN VITRO)nNOT ASSOCIATED WITH VIRUSESProtein Products of Oncogen

5、esnOncoproteinsnResemble normal products except:nDevoid of regulatory elementsnProduction does not depend on growth factors or external signalsnEffect key proteinsnCell growthnDevelopmentnDifferentiationnCell DeathPROTO-ONCOGENESnGrowth Factorsnsis, hst-1, int-2nOver expressed nGrowth Factor Recepto

6、rs nret, c-erb B-2 (Her2/neu)nMutated “on”nSignal Transducers nras: Most common abnormalitynMutated “on”nNuclear Transcription ProteinsnmycnControl transcription genes, Bind DNAnCyclin and Cyclin-Dependent KinasesnMutations favor proliferationModel of Action of ras GeneKumar et al. Basic Pathology 6

7、th ed. Fig. 6-17Role of Cyclins and Cyclin-Dependant Kinases (CDK)Cell Cyclecdk- Constitutively expressedKumar et al. Basic Pathology 6th ed. Fig. 6-18PROTO-ONCOGENE ACTIVATIONnPOINT MUTATIONSnras - COLON CANCERnGENE REARRANGEMENTSnt(8;14) - BURKITTSnt(9;22) Chronic myelogenous leukemia (CML)nGENE A

8、MPLIFICATIONnN-myc - NEUROBLASTOMABURKITTS LYMPHOMAnONCOGENE ACTIVATION BY CHROMOSOME REARRANGEMENTnTRANSLOCATION OF 8 AND 14 t(8,14)nc-myc (chr 8) to immunoglobulin heavy chain (chr 14)Department of Pathology, Kansas web siteBurkitts LymphomaKumar et al. Basic Pathology 6th ed. Fig. 6-18Department

9、of Pathology, Kansas web siteChronic Myelogenous LeukemianRECIPROCAL TRANSLOCATION BETWEEN LONG ARMS OF CHR 22 AND 9nt(9;22), PHILADELPHIA CHROMOSOME (Ph1)nMUTATION AND ACTIVATION OF CANCER CAUSING GENEnc-able to bcr = hybrid gene with tyrosine kinase activityDepartment of Pathology, Utah web siteCh

10、ronic Myelogenous Leukemiabcr-abl gene productKumar et al. Basic Pathology 6th ed. Fig. 6-19Department of Pathology, Utah web siteNEUROBLASOMAnONCOGENE ACTIVATION BY GENE AMPLIFICATIONnN-mycnDOUBLE MINUTES (DMS)nHOMOGENEOUSLY STAINING REGIONS (HSRS)nLEVEL OF AMPLIFICATION CORRELATES TO AGGRESSIVENES

11、S OF TUMORGene Amplification:NeuroblastomaKumar et al. Basic Pathology 6th ed. Fig. 6-20TUMOR SUPPRESSOR GENESnEXERT ONCOGENIC INFLUENCE WHEN DELETED OR INACTIVATEDnNEED MUTATION OF BOTH ALLELESnLOSS OF HETEROZYGOSITYnNORMALLY SUPPRESS UNCONTROLLED GROWTHnRb (RETINOBLASTOMA)np53 (70% OF ALL CANCERS)

12、nWT-1 (WILMS TUMOR)RETINOBLASTOMAnLOSS OR INACTIVATION OF TUMOR SUPPRESSOR GENEnINTERSTITIAL DELETION -13q14nLOCATION OF Rb GENEnHOMOGENOUS MUTATION OR LOSS(KNUDSONS TWO HITS)Department of Pathology, Kansas web siteKNUDSONS TWO MUTATION HYPOTHESISFAMILIAL RETINOBLASTOMA1. FIRST MUTATION IS INHERITED

13、 (GERMLINE)2. SECOND MUTATION OCCURS LATER (2nd HIT)Pathogenesis of RetinoblastomaFamilialSporadicHit #1 (inherited)Hit #2Hit #1Hit #2Kumar et al. Basic Pathology 6th ed. Fig. 6-21Department of Pathology, Kansas web siteProtein Products of Tumor Suppressor GenesnGrowth Inhibitory FactorsnBRCA-1, BRC

14、A-2nRegulate Cell AdhesionnDeleted in Colon Cancer (DCC)nCadherinsnAPCnMolecules that Regulate Signal TransductionnNF-1nMolecules that Regulate Nuclear Transcription and Cell CyclenRb nP53: Molecular policeman, Li-Fraumeni syndromeRole of pRb in Cell CycleKumar et al. Basic Pathology 6th ed. Fig. 6-

15、22Role of p53Normal CellLoss of p53Kumar et al. Basic Pathology 6th ed. Fig. 6-23Regulation of Cell DeathProliferation: MalignancyP53: Molecular PolicemanKumar et al. Basic Pathology 6th ed. Fig. 6-24APOPTOSIS = PROGRAMMED CELL DEATH (PCD)nTERMINAL EVENTS OF PCDnDNA FRAGMENTATION nCYTOPLASMIC PROTEA

16、SES ARE INVOLVED (ICE FAMILY OF PROTEASES)nAPOPTOSIS IS A CYTOPLASMIC EVENTnNOT THE SAME AS NECROSISnE.G. BCL-2 BLOCKS PCDGenes that Regulate DNA RepairnNormal cells can repair DNA damagenSet of complex DNA repair genes/proteinsnCells with abnormal (mutated) DNA repair genesnIncreased number of muta

17、tionsnIncreased risk of developing carcinomanInherited recessive fashionAUTOSOMAL RECESSIVE SYNDROMES OF DEFECTIVE DNA REPARAIRnHEREDIATERY NON-POLYPOSIS COLON CANCER (HNPCC)nReplication error (RER) phenotypenMicrosatellite instabilitynXERODERMA PIGMENTOSUMnBLOOMS SYNDROMEnFANCONIS ANEMIAnATAXIA TEL

18、ANGIECTASIATelomeresnTelomeres are at the end of chromosomesnShorten after each cell divisionnArrest cell in non-dividing staten“Cell Clock”nCancernReactivate TelomerasenAdds to the end of the telomerenCreate an immortal dividing cellMultistep CarcinogenesisnMultiple Genetic Alterations are Required for CarcinogenesisnExample Colorectal CarcinomanGatekeeper genesnRegulate entry into multistep carcinogenesisnRb, NF-1, VHL or APCnRegulate cell growthnRequire o