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how cellular oncogenes ariseproteins produced by oncogenes

2. How cellular oncogenes arise. 3. Cellular oncogenes arise from proto-oncogenes. Proto-oncogenes are not bad genesNormal genes for regulation of cell proliferation and survivalWhen it change the structure and activity by mutation: causing cancerGain-of-function mutation. 4. Cellular oncogenes were initially detected in gene transfer experiments.

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how cellular oncogenes ariseproteins produced by oncogenes

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    2. 2 How cellular oncogenes arise

    3. 3 Cellular oncogenes arise from proto-oncogenes Proto-oncogenes are not bad genes Normal genes for regulation of cell proliferation and survival When it change the structure and activity by mutation: causing cancer Gain-of-function mutation

    4. 4 Cellular oncogenes were initially detected in gene transfer experiments Gene transfer test: Isolate tumor cells DNA ? introduce into normal cells ? transformation test In 1980S, human bladder cancers DNA ? mouse cells ? cancer Gene cloning techniques: gene size fragment of DNA First human cellular oncogene: RAS oncogen Cellular oncogene and viral oncogene RAS oncogene and v-ras Cellular oncogene arise mechanism: point mutation (2) gene amplification (3) chromosomal translocation (4) DNA rearrangement (5) insertional mutagenesis

    5. 5 Mechanism 1: point mutation can convert proto-oncogenes into oncogenes Difference of normal RAS gene (proto-oncogene) and abnormal RAS gene (an oncogene): a single nucleotide base (F. 9-1) RAS oncogene point mutation is detected in cancer of bladder, lung, colon, pancrease, and thyroid Mutation of RAS gene by carcinogens: asbestos, vinyl chloride, dimethylbenzanthracene RET gene ? RET oncogene (by point mutation) ? abnormal Ret receptor protein

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    7. 7 Mechanism 2: gene amplification can convert proto-oncogenes into oncogenes Replicating of DNA in specific chromosome region F. 9-2 The main types examined by light microscopy: homogeneously staining regions (HSRs) and double minutes (DMs) Amplified DNA containing from several dozen to several hundred copies of one or more genes Most amplified genes are actively expressed Produce normal but excessive protein MYC gene family: MYC, MYCL, MYCN By gene amplification for human cancer F. 9-3

    8. 8 ERBB2 gene amplification involved in 25% of all breast and ovarian cancers MYCN gene amplication: neuroblastoma

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    11. 11 Mechanism 3: chromosomal translocation can convert proto-oncogene into oncogene Philadelphia chromosome: chromosome 22 abnormal Associated with 90% chronic myelogeneous leukemia (CML) Chromosome 9 and 22 reciprocal chromosome exchange ABL and BCR gene (F. 9-4): BCR-ABL fusion gene (in chromosome 22) fusion protein production

    12. 12 Chromosome 8 and 14 translocation: Burkitts lymphoma MYC proto-oncogene translocation Overexpression of normal Myc protein Chromosome 3-5, 6-9, 7-11, 8-16, 9-12, 12-22, 16-21 translocation for cancer development

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    14. 14 Mechanism 4: local DNA rearrangements can convert proto-oncogenes into oncogenes F. 9-5 DNA deletions, insertions, transpositions, and inversions TRK oncogene: fusion gene Trk fusion protein (F. 9-6)

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    17. 17 Mechanism 5: insertional mutagenesis can convert proto-oncogenes into oncogenes Cancer virus gene insertion

    18. 18 Summing up: cellular oncogenes arise from proto-oncogenes by mechanisms that alter gene structure or expression F. 9-7

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    20. 20 Proteins produced by oncogenes Table 9-1 Most of the proteins produced by oncogene are components of signaling pathways that promote cell proliferation and survival

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    23. 23 Oncogenes typically code for components of signaling pathways that activate cell proliferation Example: Ras-MAPK pathway (F. 9-8) One of several signaling mechanisms

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    25. 25 Some oncogenes produce growth factors v-sis oncogene (from simian sarcoma virus) Mutant form PDGF

    26. 26 Some oncogenes produce receptor proteins F. 9-9 v-erb-b oncogene: constitutively active EFG receptor (F. 9-9b) ERBB2 gene: overexpression of receptor (F. 9-9c) Jak-STAT pathway (F. 9-10) STAT ( Signal Transduction and Activators of Transcript): a cytoplasmic protein v-mpl oncogene code for a mutant receptor for thrombopoietin Trigger a Jak-STAT pathway

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    29. 29 Some oncogenes produce plasma membrane G protein F. 9-11 RAS proto-oncogene: HRAS, KRAS, and NRAS Point mutation: abnormal Ras protein production Hyperactive Ras protein (binding with GTP) ~30% of all human cancer KRAS is the most frequently mutated in human cancers

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    31. 31 Some oncogenes produce intracellular protein kinases Intracellular serine/threonine kinases BRAF oncogene: mutant form Raf kinase 2/3 melanomas Tyrosine kinase are also involved in intracellular signaling pathways (nonreceptor tyrosine kinase) Three examples of nonreceptor tyrosine kinases Src kinase: phosphorylated receptor Jak kinase: Chromosome 9 and 12: TEL-JAK2 fused gene Tyrosine kinase activity in Jak kinase Abl kinase ABL proto-oncogene BCR-ABL oncogene for abnormal version of the Abl tyrosine kinase Cannot trigger apoptosis

    32. 32 Some oncogenes produce transcription factors Myc protein avian leukosis virus (retro virus) Enhance normal Myc protein expression avian myelocytomatosis virus v-myc oncogene Abnormal Myc protein Epstein-Barr virus MYC gene translocation (to chromosome 14) Burkitts lymphoma Myc is just one of several transcription factors that produced by oncogenes v-fos, v-jun, v-myb, v-ets, and v-erb-a

    33. 33 Some oncogenes produce cell cycle or cell death regulators For Cdks and cyclins CDK4 gene CYCD1 gene for cyclin BCL2 gene: Bcl2 protein

    34. 34 Summing up: oncogene-induced disruptions in signaling pathways exhibit some common themes

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