MCB 252 Topic 6 A bit more about Ubiquitin Cancer Prof David Rivier MCB 252 Spring 2015 Reading Lodish Section entitled Loss of p53 Abolishes the DNA Damage Checkpoint pages 1141 1143 Exterior Activated TNF receptor I kB kinase cytoplasm Regulation of Target genes Degradation of I kB Nucleus Exposed NLSs Oncogenesis is a microevolutionary process One Hallmark of Cancer Cells Genome in cancer cells pretty messed up lost of mutations chromosomal rearrangements etc Mutations DNA Damage and DNA Repair Repair WT DNA Damage Mutation Mutations Result from DNA Damage that is not Repaired The Rate of Mutation Can be Increased in Either of Two Ways 1 By an Increase in the Rate of Damage e g smoking Repair WT DNA Damage Mutation 2 By a Decrease in the Rate of Repair Repair WT DNA Damage Mutation DNA Damage Pathway Steve Elledge P53 Cell Cycle control Regulation of apoptosis programmed cell death Genetic stability Cytoplasm P53 Nucleus Regulation of target genes P53 is a transcription factor MDM2 E3 ligase Cytoplasm MDM2 P53 P53 P53 degradation Nucleus There is very little P53 in cells P53 degradation MDM2 MDM2 Cytoplasm MDM2 Nucleus MDM2 P53 P53 UV on ati i d irra DNA damage DNA ATM Enters the nucleus and activates genes that will stop the cell cycle Activation of ATM Kinase P P53 MDM2 MDM2 has no affinity for phosphorylated P53 P21 P53 P53 is a tumor suppressor which is found mutated in more than 50 of all human cancers DNA Damage Pathway Steve Elledge ATM p53 P53 Transcriptional activation of target genes Among them is the gene coding for MDM2 P53 MDM2 MDM2 P53 P53 degradation 26 S Sustained mitogenic stimulation such as disregulation by oncogenes of the normal cell cycle controls induces the production of a tumor supressor P19 MDM2 Nucleolus P53 P19 MDM2 P19 MDM2 apoptosis P19 MDM2 P53 accumulates in the nucleus and activates a pathway that will promote cell death by apoptosis P21 P53 P53 is a tumor suppressor which is found mutated in more than 50 of all human cancers Genetic Molecular Models Regulatory pathways Circuit diagrams Step in a genetic or biochemical pathway Positive Regulation Activation Negative Regulation Inhibition Gene or control region Proteins Transcription Pr Protein Pr No Protein Comments on Pathways For Proteins A B A inhibits B A negatively regulates B when A is present and functioning it inhibits B in the absence of A B functions A B A activates B A positively regulates B when A is present and functioning it activates B B does not function in the absence of A Exterior Activated TNF receptor I kB kinase cytoplasm Regulation of Target genes Degradation of I kB Nucleus Exposed NLSs NFKB Regulatory Diagram TAK1 IKK IKB NFKB Txn New Questions How is a protein poly ubiquitinated How is a poly ubiquitinated protein degraded How does a protein enter the nucleus More generally how is the nucleo cytoplasmic trafficking regulated
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