P53 gene mutations in human tumors Greenblatt et al. (1995) Cancer Res. 54:4855 50%

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Transcript of P53 gene mutations in human tumors Greenblatt et al. (1995) Cancer Res. 54:4855 50%

  • Slide 1
  • p53 gene mutations in human tumors Greenblatt et al. (1995) Cancer Res. 54:4855 50%
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  • p53 and Ink4a are the two most frequently mutated genes in human tumors
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  • p53 (low) p53 (high) Cell cycle arrest Apoptosis Cellular Stresses (e.g. DNA damage) The Basic Paradigm of p53 Function
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  • The Discovery of p53
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  • SV40 large T protein binds to p53
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  • Li Fraumeni Syndrome An inherited neoplastic disease with autosomal dominant trait Characterised by multiple primary neoplasms in children and young adults A predominance of soft tissue sarcomas (e.g. breast)
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  • Li Fraumeni Syndrome: Childhood and Adult Onset Cancers
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  • Typical Li Fraumeni Syndrome Pedigree In approximately 70% of Li-Fraumeni cases, affected family members carry a germline mutation of one allele of the TP53 tumour suppressor gene.
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  • Inactivation of p53 in Friend murine erythroleukemia
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  • p53 Mutant Mice Develop Cancer
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  • p53 Mutations in Human Tumors are Found with High Frequency In the DNA Binding Domain In 143 families reported: point mutations (85%) deletions (9%) splice mutations (3.5%) insertions (2%)
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  • Ribbon ModelSpace Filling Model p53 Binds DNA The most common mutation changes arginine 248, colored red here. Notice how it snakes into the minor groove of the DNA (shown in blue and green), forming a strong stabilizing interaction. When mutated to another amino acid, this interaction is lost. Other key sites of mutation are shown in pink, including arginine residues 175, 249, 273 and 282, and glycine 245.
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  • p53 Binds DNA as a Tetramer
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  • p53 Functions in Cell Cycle Checkpoints
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  • p53 Mutant Cells Lack Cell Cycle Checkpoint Function
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  • p53 activates p21 (WAF1) El-Deiry et al. (1993) Cell 75:817
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  • The Structure of RAD9 BRCT domains required for oligomerization in response to DNA damage BRCT domains are found in BRCA1 Rad9 and BRCA1 both may act as scaffolds FHA domains bind specific phosphopeptides Rad53=Chk2 Toh and Lowndes, Biochem Soc Trans. 2003. 31:242-6. 1309 SCD=S/T Cluster Domain
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  • The Function of RAD9 (Rad53=chk2) (Rad9 similar to BRCA1) (Mec1=ATM) Toh and Lowndes, Biochem Soc Trans. 2003. 31:242-6.