The END

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Chapter 17

• The END!!!

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Oncogenes

• Code for components of the growth factor signal
  pathways
• Most oncogenes are either hyperactive, abnormal
  versions or overproduction of normal proteins

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6 Categories of Oncogenes

• Growth factors
• Receptors
• Plasma membrane G-proteins
• Protein kinases
• Transcription factors
• Cdk-cyclins

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Oncogene as Growth Factors

• Cells can acquire an oncogene that makes a growth
  factor cell divides without external factors
• Cells stimulate their own proliferation
• sis simian sarcoma virus encodes a altered
  subunit of PDGF
• cells divide without any activated platelets

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Oncogenes as Receptor or G-proteins

• Alter the Tyr kinase so that it is always on even
  when no ligand is bound
• constitutively active
• Alter plasma membrane G proteins that activates G
  protein such as Ras oncogene (most common)
• permanently bound to GTP and then stimulates the
  rest of the pathway

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Oncogene as Protein Kinase or Transcription Factor

• Usually Ser, Thr or Tyr kinases that activates
  Raf
• Raf oncogene codes for abnormal versions of Raf,
  always active and stimulates the rest of the
  protein kinase pathway
• Oncogenes such as myc, fos and jun make up
  transcription factors
• transcription factors get over-expressed

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Oncogenes as Cdk-Cyclins

• This is at the end of the signal transduction
  pathway
• make Cdk and cyclins
• Overproduction of Cdk-Cyclin complex pushes cells
  thru cell cycle without growth factors present
• 2 oncogenes in human cancers
• Cdk oncogene Cdk4 certain sarcomas
  (connective tissue-mesoderm)
• Cyclin oncogene CYCD1 over-expressed in some
  cancers including some breast cancers

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Exceptions to 6 Categories

• Inhibition of apoptosis
• bcl-2 codes for a protein that inhibits
  apoptosis, perpetuating cells with damaged DNA
  and cellular components to form a cancer
• NOT cell proliferation
• Interference with normal function of tumor
  suppressor genes

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Tumor Suppressor Genes

• Usually restrains cell proliferation
• Absence or inactivation can lead to cancer

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Rb Gene

• 1st tumor suppressor Rb prevents the transition
  between G1 and S phase
• Found in hereditary retinoblastoma
• deletion in chromosome 13 which alone doesnt
  cause cancer
• may have a mutation or deletion in the other
  chromosome 13
• Without the Rb, the cells can enter S phase
  without growth factors
• HPV can lead to inactivation of Rb by its E7 gene
  product and therefore possible cancer

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p53 Gene

• Most frequently mutated in human cancers, should
  protect cells from effects of DNA damage
• DNA damage causes cells to make more p53

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PO4-p53 Control

• PO4-p53 can lead to
• Cell cycle arrest initiates transcription
  factors
• activates p21 which is a Cdk inhibitor blocks
  passage thru G1 to allow repair of DNA
• activates DNA repair enzymes
• Cell death apoptosis
• Unsuccessful DNA repair leads to mitochondria
  becoming leaky for cytochrome c that causes the
  activation of capases

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DNA Damage

• DNA damage triggers ATM kinase that can
  phosphorylate p53 to stabilize it
• PO4-p53 cant interact with Mdm2 which causes the
  degradation of p53 and the release of p53 control

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Inherited p53 Defects

• Lose p53 function cause cancer due to cell
  division of damaged DNA
• People with 1 damaged p53 gene have a greater
  risk for cancer
• Li-Fraumeni syndrome tumors in early childhood

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Other p53 Defects

• Most all caused by environmental exposure to DNA
  damaging chemicals and radiation
• tobacco smoke
• Damage in 1 p53 gene may override the normal p53
• 4 copies of protein per p53 molecule
• 1 bad copy of protein may prevent the other 3
  normal copies fir functioning properly
• Also a target for HPV by E6 gene product

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Stopping Cancer Growth

• 1 in 3 develop cancer
• invasive tumor spreads to neighboring tissue
• metastatic tumor spreads to distant organs
• Treatments involve surgery, radiation and
  chemotherapy
• effective in some but also kills the healthy
  normal rapidly dividing cells

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Newer Avenues of Treatment

• Immunotherapy get immune system to attack the
  tumor and remove it
• cytokines and antibodies
• Prevent angiogenesis tumors must create a blood
  supple to maintain the size of tumor so generates
  blood vessels
• prevent blood vessel formation, tumor will starve
• Gene therapy to replace the defective genes such
  as p53