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Current time:0:00Total duration:4:44

Video transcript

tumor-suppressor genes are those genes whose protein products either have a halting effect on the regulation to 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 could lead to uncontrolled cell growth and cancer now there are several sort of categories of tumor suppressor proteins those that recognize you any 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 you have two copies for any given gene one on the chromosome that you got from your mom and one on the chromosome that 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 back up 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 you can think of this is that in mutated uncle genes 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 a rapidly developing cancer that originates from the immature cells of the retina the light detecting tissue of your eye and all 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 which 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 and 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