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GENES AND CANCER

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Title: GENES AND CANCER


1
GENES AND CANCER
  • ????? ?????? 463020349-8
  • ???????????????
  • ?????????????? ??????????????????

2
(No Transcript)
3
GENES
  • Gene ?

4
GENESDNA
5
Mutation
  • ????????????? ??????????? 2 ????????????????????
  • 1.??????????????? (base substitution)
  • Transition
  • Transversion
  • 2.frameshift mutation ????????????????????????????
    ??????????????????????
  • ?????????????????????????????????????????????????
    ???????????????????????????????????
    ??????????????????????

6
Mutation
  • Endogenous mutation ?????????????????????????????
    ?? ????????????????????????????????
    ???????????????? ?????????????????????????????????
    ??????????? ???????????????????????????????
    ?????????????????????? ???????????????????????????
    ???????????????????????
  • deamination of cytosine
  • 5-methylcytosine
  • ?????????????? DNA polymerase
  • ??????????? (free radical)??? ????????????????????
    ??????

7
Mutation
  • Deamination of 5-methylcytosine
    ??????????????????????????????????????????????????
    ???????????? ????????? cytosine ???
    5-methylcytosine ?????? deaminate ????????????
    uracil ??? thymine ???????? ???????????????????
    ??????????????????????????????? GC ???? AT
    ?????????? ?????????? cytosine ?????????? guanine
    (???????? CpG dinucleotide)

8
Acetylation and Methylation of Lysine
9
Mutation
  • Exogenous mutation ?????????????????????????????
    ????????????????????????????????????????????
    ??????????????????? ??????????????????????????????
    ??? DNA adduct ???????????? ????? DNA polymerase
    ????????????????????????????????
  • 6-methylguanine ??????????? alkylating agent
    ?????????????? ????? DNA polymerase ????????????
  • carcinogen-DNA adduct ??????????????????
    ??????????????????? DNA polymerase

10
CANCER
11
CANCER
  • ?????? (cancer)???????????????????????????????????
    ??????????????????????
  • tumor (neoplasm)
  • Beneign tumor ???????????????????????????????????
    ????? ?????? transform ???????? malignant tumor
    ???
  • Malignant tumor ?????????????? ??????????
    metastasis ???

12
CANCER
  • ??????????????????????????????????????????????????
    ????????????????????????????
  • ??????????????????????????????????????????????????
    ???????????????? multigene disease
  • ????????????????????????????????????????????????
    (multistage) ???????????????????????????????
    (initiation) ???????????????????? (promotion)
    ??????????????????????????????????????????????????
    ?????? ???????????????????????????????????????????
    ????????
  • ???????????? (oncogene)
  • ????????????? (tumor suppresser gene)
  • ??????????????????(DNA repair gene)

13
CANCER metastasis
14
?????????????????????????
  • Chemicals (e.g., from smoking), radiation,
    viruses, and heredity all contribute to the
    development of cancer by triggering changes in a
    cell's genes.
  • Chemicals and radiation act by damaging genes,
    viruses introduce their own genes into cells, and
    heredity passes on alterations in genes that make
    a person more susceptible to cancer.
  • Genes are inherited instructions that reside
    within a person's chromosomes. Each gene
    instructs a cell how to build a specific
    product--in most cases, a particular kind of
    protein.
  • Genes are altered, or "mutated," in various ways
    as part of the mechanism by which cancer arises.

15
???????????????????????
  • Autonomy ???????????????????????????????????????
  • Metastasis ??????????????????????????????????????
    ???????????????? ?????????????????????????
  • 1.??????????????????????growth factor
    ????????????
  • 2. ??????????????????????receptor
    ?????????????????????????????????????
  • 3.???? intracellular signal transduction
    ?????????????????????

16
???????????????????????
  • 4. ??????????????????????????????????????? cell
    cycle ?????????????????????????????(genomic
    instability)
  • 5.??????????? DNA (DNA repair system)
    ????????????????????????? ???????????????????????
    apoptosis

17
CELL DIVISION
18
CELL DIVISION
19
Molecular Biology of Cancer
Causation
  • 1. Oncogenes
  • 2. Tumor-Suppressor genes
  • 3. Apoptosis genes
  • 4. DNA repair genes

20
Molecular Biology of Cancer
Causation
H-ras
21
Molecular Biology of Cancer
Causation
  • 1. Oncogenes ?????????????????????????????
  • Rous sarcoma virus (RSV)
  • RNA virus
  • non acute virus
  • acute transforming virus

22
Selected example of oncogenes (Thomson Thomson,
1991).
23
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24
Oncogenes are Mutant Forms of Proto-Oncogenes
  • Oncogenes arise from the mutation of
    proto-oncogenes.
  • They resemble proto-oncogenes in that they code
    for the production of proteins involved in growth
    control.
  • However, oncogenes code for an altered version
    (or excessive quantities) of these growth-control
    proteins, thereby disrupting a cell's
    growth-signaling pathway.
  • By producing abnormal versions or quantities of
    cellular growth-control proteins, oncogenes cause
    a cell's growth-signaling pathway to become
    hyperactive.
  • To use a simple metaphor, the growth-control
    pathway is like the gas pedal of an automobile.
    The more active the pathway, the faster cells
    grow and divide. The presence of an oncogene is
    like having a gas pedal that is stuck to the
    floorboard, causing the cell to continually grow
    and divide.
  • A cancer cell may contain one or more oncogenes,
    which means that one or more components in this
    pathway will be abnormal.

25
Molecular Biology of Cancer
Causation
  • Tumor-Suppressor Genes ??????????????????????????
    ????? ????????????????????????
    ?????????????????????????????????????
    ??????????????????????????? ????
  • 1.retinoblastoma gene (RB gene)
  • 2.p53 gene

26
1.retinoblastoma gene (RB gene)
27
 retinoblastoma
  • ???????????????
  • Rb gene
  • Rb protein ??????????????? cell cycle
  • Autosomal dominance
  • Chromosome ??? 13
  • ??????????????????? cell cycle ???????
    transcription factor ????????

28
???????????? retinoblastoma protein
29
??????????????? Rb protein
  • G1 pRb ?????? E2F (transcriptional factor)
    ????????????? DNA ??????????
  • G1/sCDK ,cyclin D complex ???? phosphat ??????
    pRb
  • free E2F

30
??????????????? Rb protein
31
Transcriptional regulation of E2F-responsive genes
32
Transcriptional regulation of E2F-responsive genes
  • The retinoblastoma protein is a key protein in
    cell cycle control.
  • At the beginning of G1, Rb is hypophosphorylated
    and active.
  • At the end of G1, Rb is phosphorylated and
    inactivated by cyclin-dependent kinases.

33
Tumor-Suppressor Gene p53
  • ????????????? (mutation) ?????? p53
    ?????????????? ???????????????????????????????????
    ??????? ?????????????? 50 ?????????????????3,5,6
    ?????? p53 ??????????????????????????????????
    ??????????????????????? ??????????????????????????
    ??????????????????????? ????????????? ??????
    ??????????????????????????????????????????????????
    ????????????????????????????????????????
  • ??? p53 ??????????????????????????????????????????
    ???????????????????????????????????????????
    ?????????????????????????????????
    ????????????????????????????? ????????????????????
    ?????????? ???????????????

34
Tumor-Suppressor Gene p53
  • ??????????? 16-20 ???????
  • ????????????????? ????????????????? 17 ??????????
    17p13.116
  • ?????????? 11 exon
  • ???????????????????????????????????????? 393 ???
    ???????????????? 53 ??????????
  • ??? p53 ?????????????????????????????????????????

35
Tumor-Suppressor Gene p53
  • ??? p53 ????????????????????????????? (tumor
    suppressor gene)?????????????????????????????????
    ???????? ????????????????????? (cell cycle)
    ??????????? G1 ??????????????? S
    ???????????????????? ????????????????????????
    ???????????????? ?????????????? apoptosis
    ????????????????????????????????? ????????
    ????????????????? ????????????????????????????????
    ? p53 ???????????????? ?????????
  • ??????????????????????????????????????????????????
    ???? (transcription)?????????????????? ??????
    GADD45, MDM2, WAF1/Cip1 ???????????????????? p53
    ?????????????????????????????????
    ?????????????????????? ???????????????????????????
    ?????

36
Tumor-Suppressor Gene p53
37
???????????? p53 protein
38
??????????????? p53 protein
39
Translocations
  • Translocations are the transfer of a piece of one
    chromosome to a nonhomologous chromosome.
  • Translocations are often reciprocal that is, the
    two nonhomologues swap segments.

40
Translocations
  • the breakpoint may occur within a gene creating a
    hybrid gene. This may be transcribed and
    translated into a protein with an N-terminal of
    one normal cell protein coupled to the C-terminal
    of another.
  • the Philadelphia chromosome found so often in
    the leukemic cells of patients with chronic
    myelogenous leukemia (CML) is the result of a
    translocation which produces a compound gene
    (bcr-abl).

41
The Philadelphia Chromosome (Ph1)
42
Translocations
43
The Philadelphia Chromosome (Ph1) Micrograph
courtesy of Douglas C. Tkachuk.
  • This micrograph uses fluorescence in situ
    hybridization (FISH) to reveal the ABL DNA (red)
    and the BCR DNA (green) in the interphase nuclei
    of the leukemic cells of a patient with CML.
  • The red dot at left center reveals the location
    of ABL on the normal chromosome 9 the green dot
    (top center) shows BCR on the normal chromosome
    22.
  • The combined dots (red green yellow) at the
    lower right reveal the fused BCR-ABL gene on the
    Philadelphia chromosome.

44
KaryotypesThe Philadelphia Chromosome (Ph1)
45
The Philadelphia Chromosome Micrograph
courtesy of Douglas C. Tkachuk.
  • chromosomeThe view on the right side of the
    schematic below should help you interpret the
    micrograph.

46
Translocations
  • Transcription and translation of the hybrid
    BCR-ABL gene produces an abnormal ("fusion")
    protein that activates constitutively (all the
    time) a number of cell activities that normally
    are turned on only when the cell is stimulated by
    a growth factor,such as platelet-derived growth
    factor (PDGF).

47
DNA Repair Genes
  • DNA Repair Genes A third type of genes implicated
    in cancer are called "DNA repair genes.
  • DNA repair genes code for proteins whose normal
    function is to correct errors that arise when
    cells duplicate their DNA prior to cell division.
  • Mutations in DNA repair genes can lead to a
    failure in repair, which in turn allows
    subsequent mutations to accumulate.
  • People with a condition called xeroderma
    pigmentosum have an inherited defect in a DNA
    repair gene.
  • As a result, they cannot effectively repair the
    DNA damage that normally occurs when skin cells
    are exposed to sunlight, and so they exhibit an
    abnormally high incidence of skin cancer. Certain
    forms of hereditary colon cancer also involve
    defects in DNA repair.

48
DNA Repair Agents that Damage DNA
  • Certain wavelengths of radiation
  • ionizing radiation such as gamma rays and x-rays
  • ultraviolet rays, especially the UV-C rays (260
    nm) that are absorbed strongly by DNA but also
    the longer-wavelength UV-B that penetrates the
    ozone shield
  • Highly-reactive oxygen radicals produced during
    normal cellular respiration as well as by other
    biochemical pathways.
  • Chemicals in the environment
  • many hydrocarbons, including some found in
    cigarette smoke Link to description of a test
    measuring the mutations caused by the hydrocarbon
    benzopyrene.
  • some plant and microbial products, e.g. the
    aflatoxins produced in moldy peanuts
  • Chemicals used in chemotherapy, especially
    chemotherapy of cancers

49
Agents that Damage DNA
50
Agents that Damage DNA
  • betanaphthylamine
  • 1,8-DINITROPYRENE

  • Chlorozotocin

51
DNA Repair
  • A failure to repair DNA produces a
  • mutation

52
DNA Repair Types of DNA Damage
  • All four of the bases in DNA (A, T, C, G) can be
    covalently modified at various positions.
  • One of the most frequent is the loss of an amino
    group ("deamination") resulting, for example,
    in a C being converted to a U.
  • Mismatches of the normal bases because of a
    failure of proofreading during DNA replication.
  • Common example incorporation of the pyrimidine U
    (normally found only in RNA) instead of T.
  • Breaks in the backbone.
  • Can be limited to one of the two strands (a
    single-stranded break, SSB) or
  • on both strands (a double-stranded break (DSB).
  • Ionizing radiation is a frequent cause, but some
    chemicals produce breaks as well.
  • Crosslinks Covalent linkages can be formed
    between bases
  • on the same DNA strand ("intrastrand") or
  • on the opposite strand ("interstrand").
  • Several chemotherapeutic drugs used against
    cancers crosslink DNA

53
DNA RepairRepairing Damaged Bases
  • Damaged or inappropriate bases can be repaired by
    several mechanisms
  • Direct chemical reversal of the damage
  • Excision Repair, in which the damaged base or
    bases are removed and then replaced with the
    correct ones in a localized burst of DNA
    synthesis. There are three modes of excision
    repair, each of which employs specialized sets of
    enzymes.
  • Base Excision Repair (BER)
  • Nucleotide Excision Repair (NER)
  • Mismatch Repair (MMR)

54
DNA Repair Direct Reversal of Base Damage
  • Perhaps the most frequent cause of point
    mutations in humans is the spontaneous addition
    of a methyl group (CH3-) (an example of
    alkylation) to Cs followed by deamination to a T.
  • Fortunately, most of these changes are repaired
    by enzymes, called glycosylases, that remove the
    mismatched T restoring the correct C.

55
Apoptosis
  • Some viruses associated with cancers use tricks
    to prevent apoptosis of the cells they have
    transformed.
  • Several human papilloma viruses (HPV) have been
    implicated in causing cervical cancer.
  • One of them produces a protein (E6) that binds
    and inactivates the apoptosis promoter p53.
  • Epstein-Barr Virus (EBV), the cause of
    mononucleosis and associated with some lymphomas
  • produces a protein similar to Bcl-2
  • produces another protein that causes the cell to
    increase its own production of Bcl-2. Both these
    actions make the cell more resistant to apoptosis
    (thus enabling a cancer cell to continue to
    proliferate).
  • Even cancer cells produced without the
    participation of viruses may have tricks to avoid
    apoptosis.

56
Apoptosis
  • programmed cell death, is a normal cell suicide
    process in response to cell signals.
  • It is mediated by a group of gene coded
    protein-digesting enzymes called caspases that in
    an ordered series of events dismantles the
    interior of a cell.  
  • Caspases are a family of cysteine proteases

57
Apoptosis
58
Apoptosis
  • Some B-cell leukemias and lymphomas express high
    levels of Bcl-2, thus blocking apoptotic signals
    they may receive.
  • The high levels result from a translocation of
    the BCL-2 gene into an enhancer region for
    antibody production. Melanoma (the most dangerous
    type of skin cancer) cells avoid apoptosis by
    inhibiting the expression of the gene encoding
    Apaf-1.
  • Some cancer cells, especially lung and colon
    cancer cells, secrete elevated levels of a
    soluble "decoy" molecule that binds to FasL,
    plugging it up so it cannot bind Fas. Thus,
    cytotoxic T cells (CTL) cannot kill the cancer
    cells by the mechanism shown above.
  • Other cancer cells express high levels of FasL,
    and can kill any cytotoxic T cells (CTL) that try
    to kill them because CTL also express Fas (but
    are protected from their

59
Heredity Can Affect Many Types of Cancer
  • Inherited mutations can influence a person's risk
    of developing many types of cancer in addition to
    breast cancer.
  • For example, certain inherited mutations have
    been described that increase a person's risk of
    developing colon, kidney, bone, skin or other
    specific forms of cancer.

60
?????????????
  • ???? ???????????. (???.). ????????????????.
    ????????. ????????????????????????????????
  • ?????? ???????? ??????.2547.??????????????????.???
    ??????.????????????
  • ?????? ?????????????? ???????? ??????????.2544.???
    ??????????????.????????. ???.
  • ??????? ?????????????? ????? ???????????.
    2548.??? http//web.kku.ac.th/amspr/project02.htm
    . ????????????????? ?????????????????????????????
    ??????.

61
?????????????
  • ??????. ??? www.rihes.cmu.ac.th.
    ???????????????????????????? ????????????????????
  • ????? ?????????. ????????????????? AFLATOXIN. ???
    www.elib-online.com.
  • ????????? ?????????. ???????????????. ???
    www.elib-online.com.
  • ??????? ???????. ????????????? DNA. ???
    www.elib-online.com.

62
?????????????
  • P53 from http//p53.genome.ad.jp/documents/about_p
    53.html. Institute of Medical Science The
    University of Tokyo
  • common type of cancer. from
    http//www.cancer.gov/cancertopics/understandingca
    ncer/cancer/Slide39. national center institut
  • Apoptosis. From.http//users.rcn.com/jkimball.ma.u
    ltranet/BiologyPages/A/Apoptosis.htmlcancer

63
?????????????
  • Thongsuksai P. Pattern of mutations in p53 gene
    an insight into cancer molecular
    biology.Department of Pathology, Faculty of
    Medicine, Prince of Songkla University, Hat Yai,
    Songkhla, 90110, Thailand.

64
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