Chapter 9 Oncogenes Contents How Cellular Oncogenes Arise

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Contents
How Cellular Oncogenes Arise Proteins Produced by
Oncogenes
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How cellular oncogenes arise
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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

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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

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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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How Cellular Oncogenes Arise
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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

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• ERBB2 gene amplification involved in 25 of all
  breast and ovarian cancers
• MYCN gene amplication neuroblastoma

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How Cellular Oncogenes Arise
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How Cellular Oncogenes Arise
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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

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• 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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How Cellular Oncogenes Arise
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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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How Cellular Oncogenes Arise
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How Cellular Oncogenes Arise
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Mechanism 5 insertional mutagenesis can convert
proto-oncogenes into oncogenes

• Cancer virus gene insertion

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Summing up cellular oncogenes arise from
proto-oncogenes by mechanisms that alter gene
structure or expression

• F. 9-7

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How Cellular Oncogenes Arise
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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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Proteins Produced by Oncogenes
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Proteins Produced by Oncogenes
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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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Proteins Produced by Oncogenes
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Some oncogenes produce growth factors

• v-sis oncogene (from simian sarcoma virus)
• Mutant form PDGF

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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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Proteins Produced by Oncogenes
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Proteins Produced by Oncogenes
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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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Proteins Produced by Oncogenes
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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

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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

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Some oncogenes produce cell cycle or cell death
regulators

• For Cdks and cyclins
• CDK4 gene
• CYCD1 gene for cyclin
• BCL2 gene Bcl2 protein

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