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Lecture #5 Notes taken on the voice recording from the lecture. Includes pictures and figures from the powerpoint with accompanying text.

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York University
BIOL 4285
Michael Scheid

Lecture 5 Translocation of Chromatin February 11 2011IntroductionTranslocation of chromatin can lead to activation of oncogenesIn the 70s80 the models people used for cancer were birdsThere were viruses causing avian sarcomasleukemiaNo one knew the molecular events that caused cancer in birds via virusesExperiment took a virus that causes tumours in chickens and took the tumour cells from a chicken and introduced them into a rabbit implanted under the skinRabbit would break down the cells and make antibodies against the proteins present in tumour cellsWhen they put normal avian cells into rabbits they would get an array of proteins that were indicative of the antibodies raised against those cellsWhen the put in the tumours they got extra bandsproteins that they then purifiedGot three main bands and called them the small t antigen middle t antigen and large t antigenTook antibodies that the rabbit produced against these three proteins the rabbit and probed the proteins in the avian speciesThree proteins were discovered to be present there as wellThese proteins may be what is causing the tumour in avian speciesDuring cell signalling proteins go through tyrosine phosphorylationProteins undergo phosphorylation on Ser Thr and Tyr reversible post translation modification which is used for cell signalling within the cell receptor communicates to nucleus to change gene expressionThey were able to produce antibodies which recognized tyrosine phosphorylated proteins proteins that went through this were identified with antibody against tyrosine the protein then lights up on a Western blot if phosphorylatedUsed this antibody to probe the three proteins and found them to be tyrosine phosphorylatedIt turns out that many of the viral proteins that being expressed including the three had human homologs that were also tyrosine phosphorylatedIe PAGF receptor responds to growth factor becomes tyrphosphorylated and has many of the same domains as the large t antigenRealized there were viral homologs isologs to human proteins and perhaps it was the viral isoforms that were somehow mimicking the human proteins and causing cancerLed to the discovery that the PAGF receptor itself is upregulated in human cancerOnce they have the phosphortyrosine antibody and they started probing human cells they realized there was an increase in phosphotyrosine Can insert proteins that mimic the tyrosine kinase receptors but can also introduce proteins that may not be tyrosine kinases and may not become tyrphosphorylatedPerhaps proteins are inserted by viral genome that cause a transcription factor to become activatedHow can we activate that transcription factor in humans By changing the promoter upstreamIf we change the promoter we get a differential expression which leads to a change in the cells ability to prevent apoptosis and cause cell to become cancerous Article 1Studied the avian ALB virus and tumours induced by itAlso where the virus was integrating its genome where it was inserting viral promotersFound that in the leukemia the virus always had a distinct integration locus Lecture 5 Translocation of Chromatin February 11 2011 It could be the viral promoter that is landing and causing a change in the expression of an avian protein that is not normally being expressedDuring translocation of chromosomes the same thing happens there is a translocation of a promoter from one chromosome to a region on another leading to tumoursRealized that if the virus was dropping into avian genome and causing tumour then there could be a similar process in humans via translocationsSo what was being integrated Integrating on the specific site was placing a homolog of a human protein called Myc Viral Myc that is being upregulated in avian tumours Myc and a strong promoter are insterted into the avian genomeThere is a cellular homolog of Myc in humans so it may be the upregulation of Myc in humans that is playing a similar role as the viral homolog being inserted into the avian genome Article 23There were also clinical studies being done that shows there was a translocation of chromosome 8 to 14 causing Burkitts LymphomaThe Myc oncogene was on chromosome 8 and was on a locus that was being translocated to chromosome 14 cytogenetic error that is moving the cellular homolog of the viral Myc oncogene from chromosome 8 to chromosome 14Chromosome 14 has a strong promoter that causes B cells lymphoma because it codes for antibodies B cells make antibodies as a result of synthesizing a heavy and light chainThe Kappa light chain is on chromosome 14 of B cellsIn B cells there is a very strong promoter that is on all the time and Myc is mutated right in the middle of the kappa locus for the immunoglobulin light chainMyc in over expressed because it is under the control of a strong immunoglobulin promoterLosing a little bit of 8 on the q arm since its going to the q arm of 14 and vice versaBalanced translocation not addinglosing genetic materialHappens in somatic cells all the time but cell dies or the gene expression pattern is normal so there is no phenotypic differenceNo gene dosage problem since the same genetic informationamount is still there just in a different placeBecause of the translocation the Myc is right next to the Kappa light chain in the immunoglobulin locus which is turned off in every cell of the body except B cellsB cells can tolerate the upregulation of MycIf it were to happen in other somatic cells other than B cells then there maymay not be cancer depending on whether or not the phenotype of the cells provided survivalThere is no translocation of 8 to 14 in other cells because they may not tolerate the change like B cells can and therefore dieTranslocation suggests Myc is causative agent in tumours but does not prove it Article 4 1984Found that Myc was a transcription factor localized to the nucleusBinds to chromatin very tightlyIt is a basic helixloophelix transcription factorIt dimerizes with itself with and with another bHLH TF called MaxAs a dimer it has arms that chelate with DNA on palindromic sequences and binds very tightly
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