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Tumor suppressors

Created by Tracy Kim Kovach.

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  • blobby green style avatar for user Cat Mao
    Do we actually have to memorize these mechanisms for the MCAT?
    (11 votes)
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  • starky sapling style avatar for user Rissy
    What exactly does she mean by "dominant negative" at the end? Is she essentially saying that the presence of a mutated p53 protein can interfere with another normally functioning p53 protein? Thank you for the video and help!
    (10 votes)
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  • blobby green style avatar for user khanmu28
    I didn't get the last part abot mutated p53?
    (2 votes)
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    • duskpin ultimate style avatar for user Becca
      p53 proteins function in a tetramer, that is, as an assembly of 4 units. In order for the protein to work effectively, it must be 4 wildtype units. So, imagine that you have one functional copy of the gene, and one non functional copy of the gene, producing these protein units in roughly the same amount. Where A= wildtype protein and B=mutated protein

      AAAA is the only functional tetramer.

      However, you can also get AABB, AAAB, ABBB, which will not function as a tumour suppressor gene. So not only does the mutated p53 not function on its own, but it also prevents some of the wildtype p53 protein being produced from forming these functional homotetramers, wasting it in heterotetramers containing some mutated versions of the protein.
      (20 votes)
  • female robot amelia style avatar for user Gail  Golston
    SO, OK are we to assume that the majority of Tumor suppressor mutations are recessive based on what she told us about the "Two hit hypothesis". That the exceptions are the mutated p53 allele which produces a protein that ca messw ith the other normally functioning protein from another allele. Even though the p 53 mutated allele is recessive it will mess with the other Dominate normally funmctioning allele.

    Is this like an example of co-dominance or something?
    (2 votes)
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    • blobby green style avatar for user Rahul Grover
      A dominant negative phenomenon is not co-dominance. Co-dominance is a special case when both alleles "produce products" that are equally apparent in the phenotype. So if you have a wt allele and a mutated allele, you would get some wild type proteins and some mutated proteins. Dominant negative is when one allele produces a product that messes around with the product made by the normal allele. The resulting phenotype is no functional product at all.
      (8 votes)
  • female robot ada style avatar for user sokanha.kong
    It's very confusing for me at the end. When she said that p53 is "dominant negative", does it mean that "two-hit hypothesis" does not apply to p53 at all?
    (3 votes)
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  • leaf green style avatar for user gbowers
    At , when Tracy says homozygous loss of p53, does she mean mutation of both alleles?
    (2 votes)
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  • female robot grace style avatar for user Juliana Duran Delgado
    i think the correct term is suppressors not repressors
    (3 votes)
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  • blobby green style avatar for user Alex Moore
    At Tracy says that if tumor suppressor genes are not expressed, the cell cycle cannot continue. Thus:
    -- Tumor suppressor gene expressed --> cell cycle advances
    -- Tumor suppressor not expressed --> cell cycle does not advance

    In the discussion of the retinoblastoma protein (a tumor suppressor protein) at , it is the presence of this protein that inhibits cell cycle advancement. This implies:
    -- pRb gene expressed (tumor suppressor) --> cell cycle does not advance.

    This mechanism is opposite to the above. How do we reconcile this, or is this moot?
    (2 votes)
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  • blobby green style avatar for user Manar Al-Masri
    So I got that it’s essential to have mutation in both alleles to have the disorder.
    Except for P53 ? Is it always dominant negative? Or sometimes (not always)the mutated protein does his effect on the normal one?
    You’ve mentioned at “homozygous loss” is this refers to negative dominant?
    And about other kinds of tumor suppressor genes I suppose it must have “heterozygous loss” to have the cancer?
    (1 vote)
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    • female robot grace style avatar for user tyersome
      Based on what Tracy says at , only some mutations result in alleles of p53 that are dominant negative — note that in either case cancer is associated with a lack of normal p53 function.

      Homozygous loss means that in a cell (or tissue or organism) both alleles are "broken", and thus there is no functional protein being produced. Nonfunctional alleles are a very common type of recessive allele.

      Heterozygous loss of a tumor suppressor gene will usually only have visible effects if there is a protein being made that interferes with the non-mutant protein (i.e. in the case of a dominant negative allele like some p53 alleles).

      ( I found a few minutes to look at these videos and do some other reading.)
      (1 vote)
  • blobby green style avatar for user tathyapatel98
    So does the two-hit hypothesis means that even if one allele of the tumor suppressor gene is mutated we still have a backup second allele which can code for the tumor suppressor protein and protect us?
    (1 vote)
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Video transcript

Voiceover: Tumor suppressor genes are those genes whose protein products either have a halting effect on the regulation of the cell cycle, or they can also promote apoptosis, or sometimes both. So in other words these proteins are like big stop signs that act as safety checks to help stop the mistakes in cell division that can lead to uncontrolled cell growth and cancer. Now there are several sort of categories of tumor suppressor proteins. Those that recognize DNA damage and either repair it or initiate program cell death, apoptosis if it can't be repaired, so DNA repair proteins. Then there are those proteins that act as repressors of genes that are essential for the continuation of the cell cycle. So if these genes are actively repressed, and thus not expressed, the cell cycle does not continue on. So you have cell cycle repressors. With tumor suppressors there is this concept called the "Two-Hit Hypothesis." In which both alleles, and remember that alleles are basically the copies for a certain gene. And you have two copies for any given gene. One on the chromosome you got from your mom. And one on the chromosome you got from your dad. Now in the Two-Hit Hypothesis both alleles must be mutated before the effect is manifested. Because if only one of the alleles for the gene is damaged. Then you have this, sort of backup second copy, that can still produce the protective protein. So you need two hits. One hit for each of the alleles that you have. Another way that you can think of this is that in mutated oncogenes these alleles are typically dominant. So a mutation only one of the alleles yields the cancerous phenotype. But with a mutated tumor suppressor allele these mutations are recessive. Because both alleles must be mutated in order to lead to the cancerous phenotype. The Two-Hit Hypothesis was first proposed with cases of Retinoblastoma. Rapidly developing cancer that originates from the immature cells of the retina. The light detecting tissue of your eye. And I'll write this as pRb for Retinoblastoma protein. Now the Retinoblastoma protein prevents the cell from replicating when its DNA is damaged. And it does this by preventing progression of the cell cycle from G1 into the S phase or synthesis phase. So the Retinoblastoma protein binds and inhibits transcription factors. Which normally push the cell into the S phase. And this complex acts as a growth suppressor and so the cell remains in the G1 phase. This complex also attracts a histone deacetylase protein to the chromatin. Which reduces transcription of S phase promoting factors. And you can remember this by recalling that histone deacetylase leads to chromatin condensation. Or transcriptionally inactive chromatin. So this also further suppresses DNA synthesis. Another very well known tumor suppressor protein is the p53 protein. Homozygous loss of this protein is found in up to 65% of colon cancers, 50% of lung cancers, and also in breast cancers. So this is clearly a very critical tumor suppressor protein. And so p53 activates DNA repair proteins when DNA has sustained damage. And it can also arrest growth by holding the cell cycle hostage, if you will, at the G1 to S regulation point. And this gives DNA repair proteins some time to fix the damage and allow for continuation of the cell cycle. So specifically p53 binds DNA and activates several genes including ones that code for protein called p21, whichs binds the cyclin-CDK or cyclin-dependent kinase complex, which is actually the complex responsible for pushing the cell from the G1 to S phase in the cell cycle. P53 also functions in the initiation of apoptosis if the damage to DNA is irreparable. One significant exception to the Two-Hit rule for tumor suppressor genes is with certain mutations of the p53 gene product. Which can then result in what is called a "Dominant Negative." Meaning that a mutated p53 protein can prevent the protein product of the normal allele from functioning. So don't forget to sort of keep that in the back of your mind when you're thinking about tumor suppressor genes.