Chapter 9,10,11

Chapter 9,10,11 - Chapter 9: p53 and Apoptosis P53 prevents...

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Chapter 9: p53 and Apoptosis P53 prevents the proliferation of damaged cells. o Enforces cell-cycle checkpoints o Initiates DNA repair pathway if damage is detected o Promotes apoptosis if damage is severe o Cell damage initiates a kinase cascade stress signal, activating p53 (transcription factor), which enters the nucleus and promotes target genes including the CDKI p21 o P53 activity is lost in greater than 50% of cancers by somatic mutation or deletion P53 -/- mice are born normal, but most develop lymphomas within 6 months P53 can be signaled by a lack of nucleotides, UV radiation, ionizing radiation, oncogene signaling, hypoxia, or blockage of transcription. o P53 will then promote cell-cycle arrest, DNA repair, block of angiogenesis, or apoptosis In a resting, unstressed cell, p53 is actively transcribed but maintained at low levels. o Mdm2 is a p53 specific ubiquitin ligase that is actually one of p53’s target genes (‘futile cycle”) o In response to stress, p53 is rapidly phosphorylated (by stress kinases ), no longer being destroyed by mdm2-mediated proteasomal degradation. Phosphorylation of p53 changes the shape of it’s amino terminal , which is it’s mdm2- binding domain. The marjority of p53 mutations are missense mutations which are substitutions of one amino-acid for another. o They are usually clustered in the DNA-binding domain, inactivating p53. A mutation at codon 175 creates a structural mutant , disabling p53 from folding properly. A mutation at codons 248 or 273 create a contact mutant , which is a mutation at the point where p53 makes direct contact with the double helix. P53’s Structural Domains: o DNA-Binding Domain - Binds to specific elements within regulatory regions of target genes o Trans-Activation Domain - Recruits transcription factors and accessory proteins to form activating or inhibiting complexes o Telomerization (oligo) Domain - p53 functions as a tetramer (4 proteins) A mutation in one p53 allele can produce a phenotype, even in the presence of a wt allele. o P53 is a dominant-negative or dominant-interfering allele. o This is because it functions as a tetramer, and inactivation of one of the 4 proteins that make it up would cause a phenotype. Oncogenic signaling upregulates the transcription factor E2F , which induces the ARF Protein . o ARF protein interferes with mdm2, leading to stabilization of p53 and either arrest or apoptosis.
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o ARF is the product of p16(CDKI) via an A lternate R eading F rame. o ARF binds to mdm2 and keeps it in the nucleolus, making it unable to degrade p53. Apoptosis
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Chapter 9,10,11 - Chapter 9: p53 and Apoptosis P53 prevents...

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