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    Tumor Suppressor Gene

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    Tumor suppressor genes help protect cells from cancer by encoding proteins that repress cell cycle progression, couple the cell cycle to DNA damage repair, and initiate apoptosis when damage cannot be repaired. These genes generally require both copies to be mutated or inactivated before their protective effects are compromised, following the "two-hit hypothesis." Key tumor suppressors include p53 and PTEN, which are inactivated in many cancer types through mutations that disable their cell regulatory functions.

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    Tumor Suppressor Gene

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    ZiedTriki
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    Tumor suppressor genes help protect cells from cancer by encoding proteins that repress cell cycle progression, couple the cell cycle to DNA damage repair, and initiate apoptosis when damage cannot be repaired. These genes generally require both copies to be mutated or inactivated before their protective effects are compromised, following the "two-hit hypothesis." Key tumor suppressors include p53 and PTEN, which are inactivated in many cancer types through mutations that disable their cell regulatory functions.

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    Tumor suppressor genes help protect cells from cancer by encoding proteins that repress cell cycle progression, couple the cell cycle to DNA damage repair, and initiate apoptosis when damage cannot be repaired. These genes generally require both copies to be mutated or inactivated before their protective effects are compromised, following the "two-hit hypothesis." Key tumor suppressors include p53 and PTEN, which are inactivated in many cancer types through mutations that disable their cell regulatory functions.

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    68 views3 pages

    Tumor Suppressor Gene

    Uploaded by

    ZiedTriki
    Tumor suppressor genes help protect cells from cancer by encoding proteins that repress cell cycle progression, couple the cell cycle to DNA damage repair, and initiate apoptosis when damage cannot be repaired. These genes generally require both copies to be mutated or inactivated before their protective effects are compromised, following the "two-hit hypothesis." Key tumor suppressors include p53 and PTEN, which are inactivated in many cancer types through mutations that disable their cell regulatory functions.

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    Tumor suppressor gene

    A tumor suppressor gene, or antioncogene, is a gene


    that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. The loss
    of these genes may be even more important than protooncogene/oncogene activation for the formation of many
    kinds of human cancer cells.[1] Tumor suppressor genes
    can be grouped into categories including caretaker genes,
    gatekeeper genes, and landscaper genes; the classication schemes are evolving as medicine advances, learning from elds including molecular biology, genetics, and
    epigenetics.

    (C)

    Knudson two-hit model


    (tumour suppressor gene)
    high

    disease severity

    medium

    cancer
    susceptibility
    state

    2nd mutation

    medium

    2 Functions

    50%
    (1 allele)

    100%
    (2 alleles)

    0%
    (0 allele)

    expression level
    (B)

    50%
    (1 allele)

    100%
    (2 alleles)

    expression level
    (D)

    Haploinsuciency model
    (tumour suppressor gene)
    high

    2nd mutation
    medium

    Dose responsive model


    (oncogene)

    disease severity

    disease severity

    Tumor-suppressor genes, or more precisely, the proteins


    they code for, either have a dampening or repressive
    eect on the regulation of the cell cycle or promote
    apoptosis, and sometimes do both. The functions of
    tumor-suppressor proteins fall into several categories including the following:[5]

    no disease

    0%
    (0 allele)

    medium

    Dose responsive model


    (tumour suppressor gene)

    1st mutation

    no disease

    high

    Other tumor-suppressor genes that are exceptions to the


    two-hit rule are those that exhibit haploinsuciency,
    including PTCH in medulloblastoma and NF1 in
    neurobroma. An example of this is the p27Kip1 cellcycle inhibitor, in which mutation of a single allele causes
    increased carcinogen susceptibility.[4]

    Two-hit hypothesis
    (A)

    high

    There are exceptions to the two-hit rule for tumor suppressors, such as certain mutations in the p53 gene product. p53 mutations can function as a dominant negative,
    meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele.[3]

    disease severity

    netics, implying that two independent genetic events were


    necessary. He recognized that this was consistent with
    a recessive mutation involving a single gene, but requiring biallelic mutation. Oncogene mutations, in contrast,
    generally involve a single allele because they are gain-offunction mutations.

    1. Repression of genes that are essential for the continuing of the cell cycle. If these genes are not
    expressed, the cell cycle does not continue, eectively inhibiting cell division.

    1st mutation
    no disease

    no disease

    0%
    (0 allele)

    50%
    (1 allele)

    100%
    (2 alleles)

    expression level
    discrete model

    100%
    (2 alleles)

    150%
    (3 alleles)

    2. Coupling the cell cycle to DNA damage. As long


    as there is damaged DNA in the cell, it should not
    divide. If the damage can be repaired, the cell cycle
    can continue.

    200%
    (4 alleles)

    expression level
    continuum model

    Models of tumour suppression

    3. If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove
    the threat it poses for the greater good of the organisms produced

    Unlike oncogenes, tumor suppressor genes generally follow the "two-hit hypothesis, which implies that both alleles that code for a particular protein must be aected
    before an eect is manifested. This is because if only one
    allele for the gene is damaged, the second can still produce the correct protein. In other words, mutant tumor
    suppressors alleles are usually recessive whereas mutant
    oncogene alleles are typically dominant.

    4. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are
    known as metastasis suppressors.[6][7]

    The two-hit hypothesis was rst proposed by A.G. Knudson for cases of retinoblastoma.[2] Knudson observed that
    the age of onset of retinoblastoma followed 2nd order ki-

    5. DNA repair proteins are usually classied as tumor


    suppressors as well, as mutations in their genes increase the risk of cancer, for example mutations
    1

    EXTERNAL LINKS

    in HNPCC, MEN1 and BRCA. Furthermore, increased mutation rate from decreased DNA repair
    leads to increased inactivation of other tumor suppressors and activation of oncogenes.[8]

    [2] Knudson AG (1971). Mutation and Cancer: Statistical Study of Retinoblastoma. Proc Natl Acad of Sci 68
    (4): 8203. doi:10.1073/pnas.68.4.820. PMC 389051.
    PMID 5279523.

    Examples

    [3] Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. (1990). Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249 (4971):
    9125. doi:10.1126/science.2144057. PMID 2144057.

    The rst tumor-suppressor protein discovered was the


    Retinoblastoma protein (pRb) in human retinoblastoma;
    however, recent evidence has also implicated pRb as a
    tumor-survival factor.

    [4] Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ


    (1998). The murine gene p27Kip1 is haplo-insucient
    for tumour suppression. Nature 396 (6707): 17780.
    doi:10.1038/24179. PMID 9823898.

    Another important tumor suppressor is the p53 tumorsuppressor protein encoded by the TP53 gene. Homozygous loss of p53 is found in 65% of colon cancers, 3050% of breast cancers, and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic
    tumors. Abnormalities of the p53 gene can be inherited
    in Li-Fraumeni syndrome (LFS), which increases the risk
    of developing various types of cancers.

    [5] Sherr CJ (January 2004). Principles of tumor suppression. Cell 116 (2): 23546. doi:10.1016/S00928674(03)01075-4. PMID 14744434.

    PTEN acts by opposing the action of PI3K, which is essential for anti-apoptotic, pro-tumorogenic Akt activation.
    As costs of DNA sequencing have diminished, many cancers have now been sequenced for the rst time, revealing novel tumor suppressors. Among the most frequently
    mutated genes are components of the SWI/SNF chromatin remodeling complex, which are lost in about 20%
    of tumors.[9]
    Other examples of tumor suppressors include pVHL,
    APC, CD95, ST5, YPEL3, ST7, and ST14.

    See also
    Metastasis suppressor
    Adenomatosis polyposis coli
    Oncogene
    Cancer
    DNA repair
    Signal transduction
    Von Hippel Lindau Binding protein 1
    BRCA1
    p53

    References

    [1] Weinberg, Robert A (2014). The Biology of Cancer.


    Garland Science, page 231.

    [6] Yoshida BA, Sokolo MM, Welch DR, RinkerSchaeer CW (November 2000). Metastasis-suppressor
    genes: a review and perspective on an emerging
    eld. J. Natl. Cancer Inst. 92 (21): 171730.
    doi:10.1093/jnci/92.21.1717. PMID 11058615.
    [7] Hirohashi S, Kanai Y (2003). Cell adhesion system and
    human cancer morphogenesis. Cancer Sci 94 (7): 575
    81. doi:10.1111/j.1349-7006.2003.tb01485.x. PMID
    12841864.
    [8] Markowitz S (November 2000). DNA repair defects inactivate tumor suppressor genes and induce hereditary and
    sporadic colon cancers. J. Clin. Oncol. 18 (21 Suppl):
    75S80S. PMID 11060332.
    [9] Shain, AH; Pollack, JR (2013).
    The spectrum of SWI/SNF mutations, ubiquitous in human cancers..
    PLoS ONE 8 (1):
    e55119.
    doi:10.1371/journal.pone.0055119.
    PMC 3552954.
    PMID 23355908.

    6 External links
    TCF21 gene discovery at Ohio State University
    Drosophila Oncogenes and Tumor Suppressors The Interactive Fly
    Online book: Tumor Suppressor Genes, published
    in 2012
    Tumor Suppressor Gene Database, published in
    2012

    Text and image sources, contributors, and licenses

    7.1

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    Tumor suppressor gene Source: http://en.wikipedia.org/wiki/Tumor%20suppressor%20gene?oldid=630249842 Contributors: Magnus


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    7.2

    Images

    File:Models_of_tumour_suppression.svg Source:
    http://upload.wikimedia.org/wikipedia/commons/a/a3/Models_of_tumour_
    suppression.svg License: CC BY-SA 3.0 Contributors: Emmanuel Barillot, Laurence Calzone, Philippe Hup, Jean-Philippe Vert, Andrei
    Zinovyev, Computational Systems Biology of Cancer Chapman & Hall/CRC Mathematical & Computational Biology , 2012 Original
    artist: Philippe Hup

    7.3

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    Creative Commons Attribution-Share Alike 3.0

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